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Review

Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer

by
Carla L. Alves
1 and
Henrik J. Ditzel
1,2,3,*
1
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark
2
Department of Oncology, Institute of Clinical Research, Odense University Hospital, 5000 Odense, Denmark
3
Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(5), 4522; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054522
Submission received: 31 January 2023 / Revised: 13 February 2023 / Accepted: 22 February 2023 / Published: 24 February 2023
(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)
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Abstract

:
The frequent activation of the PI3K/AKT/mTOR pathway and its crucial role in estrogen receptor-positive (ER+) breast cancer tumorigenesis and drug resistance has made it a highly attractive therapeutic target in this breast cancer subtype. Consequently, the number of new inhibitors in clinical development targeting this pathway has drastically increased. Among these, the PIK3CA isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Nevertheless, the clinical development of multiple inhibitors of the PI3K/AKT/mTOR pathway, in parallel with the incorporation of CDK4/6 inhibitors into the standard of care treatment in ER+ advanced breast cancer, has led to a multitude of available therapeutic agents and many possible combined strategies which complicate personalizing treatment. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer.

1. Introduction

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway is involved in various crucial cellular functions such as growth, proliferation, metabolism and survival [1,2]. Activation of this signaling pathway is triggered by receptor tyrosine kinases (RTK) or G protein-coupled receptors (GPCR) located at the plasma membrane, which induce the recruitment of class I PI3K protein by adaptor proteins, such as insulin receptor substrate (IRS). This leads to conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) (Figure 1). PIP3 functions as a second messenger that recruits and activates AKT, which phosphorylates and inactivates tuberous sclerosis complex (TSC) 1/2, a negative regulator of mTORC1. Ultimately, activation of mTORC1 induces S6- and 4E-BP1-mediated protein and lipid synthesis and decreased autophagy, resulting in cell growth and proliferation. Importantly, mTORC1 regulates a negative feedback loop that prevents overactivation of the pathway at AKT. The downstream effects of PI3K activation can be antagonized by the tumor suppressor phosphatase and tensin homolog (PTEN) through dephosphorylation of PIP3 back to PIP2 [2,3]. Activation of RTK and GPCR also induces RAS/RAF/MEK/ERK signaling, which further reinforces the activation of PI3K (Figure 1) [4,5,6].
Abnormal activation of the PI3K/AKT/mTOR pathway often promotes excessive cell growth and resistance to apoptosis and is commonly implicated in a wide variety of cancers [7]. Alterations of this pathway are particularly frequent in breast cancer, which remains the most common cancer and second cause of cancer death in women worldwide [8]. Indeed, approximately 70% of all breast tumors exhibit an alteration that renders the PI3K/AKT/mTOR pathway hyperactivated [9]. These often include hotspot single amino acid substitutions in the p110α subunit of the PI3K, encoded by PIK3CA [10,11]. Additionally, AKT1-3 mutations and/or amplifications, PDK1 amplification, PTEN and TSC1/2 inactivating mutation, and deletion or epigenetic silencing, which cause hyperactivation of the pathway, have also been found in breast cancer and have been suggested to hold prognostic or predictive value [10,12,13,14]. The frequency of these alterations may vary across the different breast cancer subtypes. Estrogen receptor-positive (ER+) breast cancer represents the largest breast cancer subtype and is often associated with mutations of PIK3CA at substantially higher rates than triple-negative breast cancer (TNBC). Although mutations in individual genes occur rarely, combined PIK3CA-, AKT1- and mTOR-activating mutations together with inactivation/loss of PTEN are observed in approximately 25–30% of all TNBC [10,15,16,17].

2. The Role of the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer

Interaction between the ER and PI3K/AKT/mTOR pathways occurs at multiple nodes of each pathway (Figure 2). Activation of the PI3K/AKT/mTOR pathway induces estrogen-independent ER transcriptional activity through phosphorylation of ERα by AKT or S6K1 [18,19]. Conversely, ER target gene expression activates upstream effectors of the PI3K/AKT/mTOR pathway, such as RTKs, receptor ligands and adaptors [20]. Furthermore, ER also activates the PI3K/AKT/mTOR pathway by direct binding to the p85α regulatory subunit of PI3K [21]. Approximately 30–40% of all ER+ breast tumors exhibit an activating mutation of PIK3CA, which can either increase the catalytic activity or cause the retention of the p110α subunit, thereby promoting excessive cell multiplication and resistance to apoptosis [22,23]. PIK3CA-mutated tumors have been associated with ligand-independent activation of ER, which causes poor response to antiestrogens compared to wild-type tumors [20,24]. Furthermore, activation of the PI3K/AKT/mTOR pathway has been demonstrated as a mechanism of resistance to long-term estrogen deprivation [25]. Indeed, endocrine-resistant preclinical models showed increased phosphorylation levels of PI3K and mTOR substrates, and targeted inhibition of these molecules impaired cell growth and improved response to endocrine therapy [26,27,28,29]. Conversely, compensatory ER transcriptional expression is observed following inhibition of the PI3K/AKT/mTOR signaling, and co-inhibition of ER and PI3K showed synergistic effects in ER+ PIK3CA-mutated preclinical models, supporting the coregulation of the two pathways [2,24]. Together, these data provided the rationale for clinical investigations of combined ER and PI3K/AKT/mTOR inhibition in endocrine therapy-resistant ER+ breast cancer.

3. Key Targetable Regulators of the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer

The frequent activation of the PI3K/AKT/mTOR pathway observed in ER+ breast cancer and its implication in the development of acquired endocrine resistance has made it a key target for pharmacologic intervention in this patient population. Indeed, a wide range of agents targeting regulators of this pathway have been investigated in preclinical and clinical studies, including allosteric inhibitors of mTORC1, pan- or isoform-specific PI3K inhibitors, ATP-competitive inhibitors of mTORC1/mTORC2, dual PI3K/mTOR inhibitors and allosteric or catalytic inhibitors of AKT (Table 1). Despite such efforts, only a handful of these agents have been granted approval by the FDA/EMA for the treatment of ER+ advanced breast cancer, primarily due to dose-limiting toxicity and consequent use of subtherapeutic dosages that result in incomplete pathway inhibition. Furthermore, the disruption of negative feedback loops, such as the mTORC1/S6K1 negative loop at IRS1 (Figure 1), caused by PI3K/AKT/mTOR inhibitors, paradoxically triggers activation of the pathway.

3.1. mTOR Inhibitors

mTORC1 inhibitors, such as everolimus and temsirolimus, are allosteric irreversible inhibitors of mTORC1-dependent phosphorylation of S6K1 [2,30]. Results from the BOLERO-2 and TAMRAD clinical trials showed that the addition of everolimus to either exemestane or tamoxifen was associated with longer progression-free survival (PFS) compared to either exemestane or tamoxifen alone in ER+ advanced breast cancer patients who had progressed on an aromatase inhibitor (AI) (BOLERO-2, PFS 7.8 vs. 3.2 months, p < 0.0001; TAMRAD, PFS 8.6 vs. 4.5 months, p < 0.01) [31,43]. These findings led to FDA and EMA approval of combined everolimus and endocrine therapy for metastatic ER+ breast cancer after progression on an AI. More recently, results from the PrE0102 clinical trial showed that combined everolimus and the estrogen receptor downregulator, fulvestrant, improved PFS more compared to the fulvestrant alone (10.3 vs. 5.1 months, p = 0.02) in ER+ advanced breast cancer patients previously treated with an AI [32]. However, the severe toxicity of everolimus has limited its use in the clinic. Currently, several clinical trials are evaluating the efficacy of the dual mTORC1/2 inhibitors AZD2014 and sapanisertib, which produce a more complete blockade of mTORC by inhibiting both mTORC1-dependent phosphorylation of S6K1 and mTORC2-dependent phosphorylation of AKT, and show activity in mTORC1-mutated everolimus-resistant tumors [44,45,46]. Importantly, early clinical trials investigating mTORC1/2 inhibitors found higher single-agent activity than previously observed with mTORC1 inhibitors in various solid tumors, including ER+ breast cancer [47,48].

3.2. Pan-PI3K Inhibitors

Several pan-PI3K inhibitors have been developed, including buparlisib, pilaralisib and pictilisib, which block all isoforms of class IA PI3Ks [49]. These agents are associated with a high toxicity profile that precludes administration of an effective dose and does not significantly improve tumor growth inhibition compared to endocrine therapy alone. Results from the phase III BELLE-2 trial showed that combined buparlisib and fulvestrant modestly improved PFS compared to fulvestrant alone in ER+ advanced breast cancer patients who progressed on an AI (6.9 vs. 5.0 months, p < 0.001) [33]. Notably, a sub-analysis in this trial showed that there was a substantial improvement in PFS for patients with PIK3CA mutations treated with the combination compared to those treated with endocrine therapy alone (7.0 vs. 3.2 months, p < 0.001). More recently, results from the phase III BELLE-3 trial showed a modest, albeit statistically significant, improvement in PFS in the combined buparlisib- and fulvestrant-treated arm compared to fulvestrant alone in ER+ advanced breast cancer patients after progression on endocrine therapy and everolimus (3.9 vs. 1.8 months, p = 0.0003) [34]. These data, together with the high rates of serious adverse effects observed with these agents, limit further clinical development of buparlisib in this patient population [5]. In the FERGI clinical study, addition of pictilisib to fulvestrant did not significantly improve PFS in ER+ advanced breast cancer resistant to treatment with an AI in the adjuvant or metastatic setting [35].

3.3. Isoform-Specific PI3K Inhibitors

Several p110α isoform-specific inhibitors have been developed, including alpelisib and taselisib [49], that block the response of the PI3K/AKT/mTOR pathway to several growth stimuli [50]. The first isoform-specific inhibitor that was clinically investigated was alpelisib, which showed preferential activity in PIK3CA-mutated tumors [51,52]. The results from the large phase III SOLAR-1 trial showed improved PFS in the group receiving combined alpelisib and endocrine therapy compared to endocrine therapy alone in PIK3CA-mutated ER+ metastatic breast cancer patients previously treated with antiestrogen therapy. This led to the approval of this combination by the FDA and EMA [36]. In contrast, the NEO-ORB trial showed no improvement in the overall response rate (ORR) and pathologic complete response (pCR) with the addition of alpelisib to letrozole in the neoadjuvant setting of either PIK3CA-mutated or wild-type ER+ early breast cancer [37]. Notably, preliminary results of the phase II BYLIEVE trial that investigated combined alpelisib and endocrine therapy (letrozole or fulvestrant) in patients with PIK3CA-mutated ER+ advanced breast cancer after progression on combined CDK4/6 inhibitor and endocrine therapy showed a longer PFS for patients previously treated with CDK4/6 inhibitor and an AI, which supported the clinical relevance of alpelisib in this subpopulation [38]. Taselisib is another PIK3CA-mutated isoform-specific inhibitor that has been evaluated in the phase III SANDPIPER trial. A modest, albeit statistically significant, improvement in PFS for combined taselisib and fulvestrant compared to fulvestrant alone was observed in patients with ER+ advanced tumors who had progressed during or after AI treatment, irrespective of the PIK3CA mutation status (7.4 vs. 5.4 months, p = 0.0037) [39]. Additionally, the phase II LORELEI trial found no significant difference in pCR between combined taselisib and letrozole versus letrozole alone as neoadjuvant treatment in patients with stage I–III, operable, ER+/HER2− negative (HER2−) breast tumors with or without PIK3CA mutation [40]. Both SANDPIPER and LORELEI trials showed high rates of serious adverse effects that resulted in treatment discontinuation in 17% and 11%, respectively, of the taselisib-treated patients and precluded further clinical development of this drug.

3.4. Pan-AKT Inhibitors

Development of isoform-specific AKT inhibitors has been challenging due to the high structural similarity between the three isoforms (AKT1/2/3) [53]. Pan-AKT inhibitors include ATP-kinase activity inhibitors, such as capivasertib and ipatasertib, and allosteric inhibitors, such as MK-2206. In the phase II FAKTION trial, combined fulvestrant and capivasertib significantly prolonged PFS compared to fulvestrant alone (10.3 months vs. 4.8 months, p = 0.0018) in patients with ER+ locally advanced or metastatic breast cancer who had relapsed or progressed on an AI [41]. Furthermore, a phase I study evaluating capivasertib as monotherapy or in addition to fulvestrant in heavily pre-treated ER+ advanced breast cancer patients harboring the AKT1 E17K mutation showed favorable activity and tolerability of capivasertib as a single agent and in the combination regimen, suggesting the potential clinical utility of capivasertib in this patient population [12]. Recently, positive results from the phase III CAPItello-291 trial evaluating capivasertib in combination with fulvestrant versus fulvestrant alone in patients with ER+ advanced breast cancer after progression on endocrine therapy, with or without an CDK4/6 inhibitor, showed that the addition of capivasertib to endocrine therapy significantly improved PFS in the overall patient population, independent of the AKT mutational status (7.2 vs. 3.6 months, p < 0.001) (7.3 vs. 3.1 months, p < 0.001) [42]. This trial is currently ongoing to investigate the effect of combined capivasertib and fulvestrant on overall survival (OS), but these encouraging findings will likely lead to FDA approval for ER+ advanced breast cancer patients who progressed on endocrine therapy with or without a CDK4/6 inhibitor.

3.5. Dual PI3K/mTOR Inhibitors

There has been an increasing interest in the clinical development of agents that provide dual inhibition of both PIK3CA and mTOR, and thus, achieve a more complete blockade by inhibiting multiple points of the PI3K/AKT/mTOR pathway and bypassing negative feedback loops associated with reduced clinical efficacy. Due to the structural similarities of PI3K and mTOR, these dual inhibitors can target the active sites of both kinases. This leads to blockage both upstream and downstream of AKT, thus avoiding the problem of AKT activation following inhibition of the mTORC1–S6K–IRS1 negative feedback loop, which has been reported with mTOC1 blockers [54]. Therefore, dual PI3K/mTOR have been associated with higher anti-tumor activity, but, unfortunately, also a higher toxicity profile [55]. Dactolisib, voxtalisib, bimiralisib and gedatolisib are some of the agents that have been evaluated in phase I/II trials [5]. Notably, gedatolisib has recently received breakthrough therapy designation by the FDA to accelerate the development and regulatory review of this agent based on data from a Phase 1b trial that assessed the safety, tolerability and clinical activity of gedatolisib in combination with endocrine therapy and CDK4/6 inhibitor in ER+ advanced breast cancer that progressed on CDK4/6 therapy and an AI [56]. Consequently, gedatolisib is being evaluated in the phase III trial VIKTORIA-1 combined with fulvestrant with or without the CDK4/6 inhibitor palbociclib in this patient population (NCT05501886).

4. Determining the Optimal Point of Inhibition of the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer

The recent explosion in the number and diversity of PI3K/AKT/mTOR inhibitors in clinical development creates the need for a rational approach to identify the tumor/patient that will benefit the most from a specific inhibitor. Thus, it is critical to identify the genomic contexts in which these various types of inhibitors show superior activity [57]. It is noteworthy that the successful introduction of these agents into the clinic is dependent on finding tolerable dosages that efficiently inhibit the pathway and achieve anti-tumor activity. Indeed, the development of compounds targeting the PI3K/AKT/mTOR pathway has been significantly precluded by the broad range of off- and on-target effects and associated toxicity, which most often include hyperglycemia, dermatitis and rashes, stomatitis, diarrhea and nausea and fatigue [58,59].
Based on early-phase clinical evidence, pan-PI3K and dual PI3K/mTOR inhibitors, by inhibiting all four isoforms of PI3K, may be better suited for tumors associated with multiple and heterogeneous molecular alterations in the PI3K/AKT/mTOR pathway [57]. Indeed, studies have shown responses to pan-PI3K inhibitors in both PIK3CA-mutated and wild-type tumors, which may exhibit pathway activation driven by molecular alterations in other pathway components [60,61]. Although pan-PI3K and dual PI3K/mTOR inhibitors are associated with similar adverse effects, more frequently reported with the latter, it is likely that the pan-PI3K inhibitors, due to their narrower activity profile and wider therapeutic window, are more suitable than dual PI3K/mTOR inhibitors for combined therapies with other targeted or cytotoxic agents [62,63,64]. Nevertheless, tumors exhibiting alterations downstream of PI3K but upstream of mTOR, such as the loss of PTEN or TSC1/2, may be more efficiently suppressed by dual PI3K/mTOR inhibitors, which target the pathway at multiple sites and thus show the broadest activity profile [65].
In contrast to pan-PI3K and dual PI3K/mTOR inhibitors, isoform-specific PI3K inhibitors exhibit a narrower activity, which make them more amenable to combination with other pathway inhibitors and may offer greater opportunities for optimized dosing and schedule of therapy [57]. Furthermore, the high selectivity of isoform-specific PI3K inhibitors implies that these agents may show higher activity in tumors with specific mutations, but a reduced efficacy in tumors with multiple PI3K/AKT/mTOR pathway alterations, and thus require biomarker-based patient selection [66,67].
AKT inhibitors may be particularly valuable in tumors with PTEN loss, which do not benefit from either pan- or isoform-specific PI3K-targeted agents [68,69,70]. Although PTEN alterations appear to be a strong indicator of AKT inhibitor efficacy, PIK3CA-mutant tumors may also benefit from AKT inhibition. The rationale for targeting PIK3CA-mutant tumors with AKT inhibitors lies in the AKT function of funneling all PI3K signaling activity [69,71]. Indeed, we and others have shown that sensitivity to AKT inhibitors was observed in both PIK3CA-mutant/PTEN-wild-type and PIK3CA-wild-type/PTEN-null breast cancer cell lines, and sensitivity to AKT inhibitors correlated with SGK and p-AKT expression levels [72,73,74,75]. Concordantly, the FAKTION trial showed that PIK3CA-mutant ER+ metastatic breast tumors benefit from combined capivasertib and fulvestrant [41]. In ER+ breast tumors with AKT1 E17K gain-of-function mutations, which promote constitutive activation of the downstream pathway, treatment with the AKT capivasertib yielded tumor regression [76]. Notably, additional genetic alterations in the PI3K/AKT/mTOR pathway were associated with prolonged PFS, suggesting that multiple alterations within the pathway might further sensitize AKT1-E17K-mutated tumors to AKT inhibitors [71]. In spite of this, it has been demonstrated that PI3K controls additional parallel, independent, oncogenic pathways, such as ERK signaling, which AKT inhibitors may fail to block [77]. Thus, not all PIK3CA-mutated breast cancer models might benefit from AKT blockers, as some may promote cell growth through an AKT-independent axis, such as PDK1/SGK3/mTORC1 [73,78]. Notably, results from recent clinical studies supported the addition of an AKT inhibitor to first-line paclitaxel treatment of TNBC with alterations in the PI3KCA/AKT1/PTEN axis [79,80]. These findings have not yet been demonstrated with other inhibitors of the PI3K/AKT/mTOR pathway [81,82].
Regarding mTORC inhibitors, dual mTORC1/2 inhibitors have demonstrated greater efficacy than mTORC1 inhibitors in clinical trials, likely due to their ability to inhibit both mTORC complexes, thus bypassing the activation of AKT by mTORC2. Furthermore, dual mTORC1/2 inhibitors function as catalytic inhibitors, in contrast to the allosteric mTORC1 inhibitors, which may explain the greater inhibitory activity against mTORC1 of some dual mTORC1/2 inhibitors compared to mTORC1 inhibitors [44]. Importantly, the profound inhibition of 4E-BP1 achieved via dual mTORC1/2 inhibition, but not with mTORC1 inhibitors, may explain the differential anti-tumor effect between these two classes of drugs [47,83,84]. However, some mTORC1/2 agents have only been capable of causing transient tumor growth inhibition, comparable to mTORC1 inhibitors, which may suggest similar mechanisms of resistance between these agents [85].

5. Combinatorial and Sequential Treatments with PI3K/AKT/mTOR Inhibitors in ER+ Breast Cancer

Although the genomic landscape of breast cancer supports development of therapeutic strategies targeting the PI3K/AKT/mTOR axis, complete blockage of this pathway remains elusive. A common limitation of all inhibitors of the PI3K/AKT/mTOR pathway is the compensatory activation of multiple upstream tyrosine kinase receptors and other compensatory mechanisms that can reactivate the PI3K pathway and impair the efficacy of these agents [71]. Therefore, optimization of drug combination regimens and biomarker-based population refinement is urgently warranted to improve clinical responses to PI3K/AKT/mTOR inhibitors in ER+ breast cancer [24,71,86].
Notably, the last few years have seen impressive improvement in the clinical outcomes of ER+ advanced breast cancer patients as a result of the incorporation of CDK4/6 and PI3K inhibitors in the standard of care treatment. Although the isoform-specific PI3K inhibitor alpelisib has proven to significantly improve PFS in PIK3CA-mutated tumors in combination with fulvestrant, this agent is associated with serious grade 3–4 adverse effects [36]. In contrast, CDK4/6 inhibitors showed improved PFS and OS compared to endocrine therapy alone in both endocrine-sensitive or endocrine-resistant tumors, with acceptable toxicity profiles, which can be successfully managed using drug dose reduction or withdrawal [87,88,89,90,91,92,93]. However, the development of resistance to CDK4/6 inhibitors is inevitable, and one of the suggested resistance mechanisms is the convergence of the cell-cycle and PI3K/AKT/mTOR pathways. Indeed, we and others have shown that upregulation of p-AKT, PDK1, p70S6K and loss of PTEN are associated with resistance to CDK4/6 inhibitors preclinically, and treatment with agents targeting the PI3K/AKT/mTOR pathway can overcome CDK4/6 inhibitor resistance [75,94,95,96].
Furthermore, the crosstalk between the ER, cyclin D-CDK4/6 and PI3K/AKT/mTOR pathways has been demonstrated extensively in preclinical studies, with cyclin D1 acting as a common node (Figure 3) [97]. Binding of cyclin D1 to CDK4/6 induces Rb phosphorylation and subsequent uncoupling from E2F, which promotes G1-S phase cell cycle progression [98]. Importantly, estrogen promotes cyclin D1 transcription and, conversely, cyclin D1 and S6K can cause ligand-independent ER transcription. Furthermore, AKT-mediated inhibition of GSK3β stabilizes cyclin D1 from proteolytic degradation [99]. Inhibition of PI3K results in enhanced ER transcriptional activity, which can be overcome, at least in part, by inhibition of CDK4/6. Conversely, treatment with an CDK4/6 inhibitor causes incomplete cell cycle arrest that can be more efficiently blocked by the addition of PI3K inhibition [95,100]. Together, the convergent effects and the complex intersection of these three interrelated pathways supported the recent clinical development of triple therapies targeting PI3K/AKT/mTOR, CDK4/6 and ER to further improve the clinical outcome in ER+ advanced breast cancer (Table 2) [97]. Most of these trials are currently enrolling patients or have just completed patient recruitment, and preliminary data have not yet been reported. Recently, a phase Ib trial testing the triple combination of CDK4/6 inhibitor palbociclib, PIK3CA-isoform-specific inhibitor taselisib and fulvestrant showed tolerability at pharmacodynamically-active doses and promising efficacy in heavily PIK3CA-mutated ER+/HER2− advanced breast cancer [101]. Disappointingly, another trial demonstrated high toxicity with a triple combination of either PIK3CA-isoform-specific inhibitor alpelisib or pan-PI3K inhibitor buparlisib with CDK4/6 inhibitor ribociclib and fulvestrant [97]. Nevertheless, numerous ongoing clinical trials are continuing to evaluate alpelisib in different triple combinations in ER+ advanced breast cancer subpopulations, and these results are crucial for definitive conclusions.
Critical questions remain to be answered: First, whether patients with PIK3CA-mutated ER+ breast cancer should receive alpelisib or CDK4/6 inhibitor plus endocrine therapy as first-line therapy in the advanced setting. Based on the final results from the MONALEESA-2/3 (CDK4/6 inhibitor ribociclib plus fulvestrant/letrozole) and SOLAR-1 (PI3K inhibitor alpelisib plus fulvestrant) trials, combined ribociclib and endocrine therapy was associated with statistically significantly longer PFS and OS, whereas combined alpelisib and fulvestrant showed a significant improvement in PFS, but the prolongation of OS did not reach statistical significance [36]. These data might favor the selection of ribociclib over alpelisib as the choice for endocrine therapy in the first-line setting, but this leads to another critical question: In order to overcome resistance to the CDK4/6 inhibitor, should patients receive upfront triple therapy with PI3K, CDK4/6 and ER blockers, or standard double combinations with ribociclib or alpelisib and, upon progression, switch to triple combination or an alternative double combination? Preclinical studies have shown that upfront triple combination with endocrine therapy, CDK4/6 and PI3K or mTOR inhibitors achieved greater cell cycle arrest, induced apoptosis and tumor regression in in vitro and in vivo CDK4/6 inhibitor-naïve models of advanced ER+ breast cancer, but not in models of acquired resistance to the CDK4/6 inhibitor [94,95]. In contrast, preliminary data from the phase II BYLieve trial, which investigates the efficacy of combined alpelisib and fulvestrant, showed that this treatment is also effective in PIK3CA-mutated tumors previously treated with the CDK4/6 inhibitor [38]. In line with this, we have recently shown that triple combination with fulvestrant, palbociclib/ribociclib and AKT inhibitor capivasertib or isoform-specific PI3K inhibitor alpelisib efficiently suppressed tumor growth in in vitro and in vivo models of resistance to combined endocrine therapy and the CDK4/6 inhibitor [75,102]. Furthermore, we showed that switching the CDK4/6 inhibitor for the AKT/PI3K inhibitor in combination with the endocrine therapy backbone did not prevent tumor outgrowth in combined endocrine- and CDK4/6 inhibitor-resistant models [75,102]. Importantly, our study showed that a double combination with fulvestrant plus either the AKT/PI3K or CDK4/6 inhibitor efficiently blocked the growth of endocrine and CDK4/6 inhibitor-sensitive cells, which exhibit lower levels of phospho-AKT compared to resistant cells [75,102]. These findings highlight the urgent need for biomarkers for patient selection to optimize PI3K/AKT/mTOR-targeted therapy in ER+ advanced breast cancer. Matured data from ongoing multi-armed randomized clinical trials incorporating biomarker-based patient stratification will be crucial to fully answer these questions.

6. Conclusions

The treatment landscape for ER+ advanced breast cancer has improved significantly with the addition of the CDK4/6 inhibitors to endocrine therapy as standard treatment. However, all patients will eventually progress on this combined therapy and new rational therapeutic strategies are required upon progression. The crucial role of the PI3K/AKT/mTOR pathway in ER+ breast cancer tumorigenesis and treatment response has been demonstrated in numerous preclinical and clinical studies. Incorporation of a PI3K/AKT/mTOR inhibitor functions synergistically with endocrine therapy and CDK4/6 inhibitors to inhibit tumor growth and prevent or overcome resistance to standard therapy in ER+ metastatic breast cancer. This has led to a dramatic increase in the number of clinical studies investigating drugs targeting this pathway, and to the approval of the mTOR inhibitor everolimus and the PIK3CA inhibitor alpelisib combined with endocrine therapy in ER+ advanced breast cancer patients previously treated with antiestrogen therapy. Although multiple regimens have been suggested in different lines of therapy, the optimal treatment sequencing and combinatorial strategy in this clinical setting remain undefined. Currently, the CDK4/6 inhibitor continues to be the preferred choice for first-line combined treatment with endocrine therapy due to its better toxicity profile compared to either alpelisib or everolimus. Upon progression on combined CDK4/6 inhibitor and endocrine therapy, subsequent combined therapy will frequently switch to a PI3K/AKT/mTOR inhibitor with endocrine therapy. In PIK3CA-mutated PTEN wild-type tumors, alpelisib or an alternative α-specific PI3K inhibitor will likely remain the first choice. For tumors with multiple alterations in the pathway, particularly PTEN loss and AKT mutations, dual PI3K-mTOR or pan-AKT inhibitors are preferred, with the latter showing the advantage of lower toxicity and better suitability to combination therapy. Nevertheless, preclinical data suggest that switching endocrine therapy partners from the CDK4/6 to PI3K/AKT/mTOR inhibitor will not be sufficient to efficiently overcome drug resistance, and tougher therapeutic strategies may be required. Indeed, upfront triple-targeted therapy might be needed in tumors pretreated with endocrine therapy, with or without the CDK4/6 inhibitor, whereas treatment-naive tumors may significantly benefit from standard double combinations. Results from ongoing randomized clinical trials investigating the optimal sequencing and combinations including these targeted agents with biomarker-based population refinement are warranted to fully optimize combinatorial strategies targeting PI3K/AKT/mTOR, CDK4/6 and ER in ER+ advanced breast cancer.

Author Contributions

C.L.A. wrote the first draft. H.J.D. modified and optimized it subsequently. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded in part by grants from the Danish Cancer Society, Health Insurance “Denmark”, and Pink Tribute.

Acknowledgments

We would like to thank M. Kat Occhipinti for editorial assistance.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Verret, B.; Cortes, J.; Bachelot, T.; Andre, F.; Arnedos, M. Efficacy of PI3K inhibitors in advanced breast cancer. Ann. Oncol. 2019, 30 (Suppl. 10), 12–20. [Google Scholar] [CrossRef] [PubMed]
  2. Bilanges, B.; Posor, Y.; Vanhaesebroeck, B. PI3K isoforms in cell signalling and vesicle trafficking. Nat. Rev. Mol. Cell Biol. 2019, 20, 515–534. [Google Scholar] [CrossRef] [PubMed]
  3. Engelman, J.A.; Luo, J.; Cantley, L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 2006, 7, 606–619. [Google Scholar] [CrossRef] [PubMed]
  4. Di Nicolantonio, F.; Arena, S.; Tabernero, J.; Grosso, S.; Molinari, F.; Macarulla, T.; Russo, M.; Cancelliere, C.; Zecchin, D.; Mazzucchelli, L. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Investig. 2010, 120, 2858–2866. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Janku, F.; Yap, T.A.; Meric-Bernstam, F. Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018, 15, 273–291. [Google Scholar] [CrossRef]
  6. De Luca, A.; Maiello, M.R.; D’Alessio, A.; Pergameno, M.; Normanno, N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: Role in cancer pathogenesis and implications for therapeutic approaches. Expert. Opin. Ther. Targets 2012, 16 (Suppl. 2), S17–S27. [Google Scholar] [CrossRef] [PubMed]
  7. Hoxhaj, G.; Manning, B.D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020, 20, 74–88. [Google Scholar] [CrossRef] [PubMed]
  8. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef]
  9. Hernandez-Aya, L.F.; Gonzalez-Angulo, A.M. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 2011, 16, 404–414. [Google Scholar] [CrossRef] [Green Version]
  10. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012, 490, 61–70. [Google Scholar] [CrossRef] [Green Version]
  11. Ciriello, G.; Gatza, M.L.; Beck, A.H.; Wilkerson, M.D.; Rhie, S.K.; Pastore, A.; Zhang, H.; McLellan, M.; Yau, C.; Kandoth, C.; et al. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell 2015, 163, 506–519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Smyth, L.M.; Tamura, K.; Oliveira, M.; Ciruelos, E.M.; Mayer, I.A.; Sablin, M.P.; Biganzoli, L.; Ambrose, H.J.; Ashton, J.; Barnicle, A.; et al. Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 (E17K)-Mutant, ER-Positive Metastatic Breast Cancer. Clin. Cancer Res. 2020, 26, 3947–3957. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Hinz, N.; Jucker, M. Distinct functions of AKT isoforms in breast cancer: A comprehensive review. Cell Commun. Signal 2019, 17, 154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Stemke-Hale, K.; Gonzalez-Angulo, A.M.; Lluch, A.; Neve, R.M.; Kuo, W.L.; Davies, M.; Carey, M.; Hu, Z.; Guan, Y.; Sahin, A.; et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008, 68, 6084–6091. [Google Scholar] [CrossRef] [Green Version]
  15. Pascual, J.; Turner, N.C. Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann. Oncol. 2019, 30, 1051–1060. [Google Scholar] [CrossRef] [Green Version]
  16. Shah, S.P.; Roth, A.; Goya, R.; Oloumi, A.; Ha, G.; Zhao, Y.; Turashvili, G.; Ding, J.; Tse, K.; Haffari, G.; et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012, 486, 395–399. [Google Scholar] [CrossRef] [Green Version]
  17. Baselga, J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 2011, 16 (Suppl. 1), 12–19. [Google Scholar] [CrossRef]
  18. Yamnik, R.L.; Digilova, A.; Davis, D.C.; Brodt, Z.N.; Murphy, C.J.; Holz, M.K. S6 kinase 1 regulates estrogen receptor α in control of breast cancer cell proliferation. J. Biol. Chem. 2009, 284, 6361–6369. [Google Scholar] [CrossRef] [Green Version]
  19. Campbell, R.A.; Bhat-Nakshatri, P.; Patel, N.M.; Constantinidou, D.; Ali, S.; Nakshatri, H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α: A new model for anti-estrogen resistance. J. Biol. Chem. 2001, 276, 9817–9824. [Google Scholar] [CrossRef] [Green Version]
  20. Miller, T.W.; Balko, J.M.; Arteaga, C.L. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J. Clin. Oncol. 2011, 29, 4452–4461. [Google Scholar] [CrossRef] [Green Version]
  21. Simoncini, T.; Hafezi-Moghadam, A.; Brazil, D.P.; Ley, K.; Chin, W.W.; Liao, J.K. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000, 407, 538–541. [Google Scholar] [CrossRef]
  22. Huang, C.H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu, V.E.; Kinzler, K.W.; Vogelstein, B.; Gabelli, S.B.; Amzel, L.M. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 2007, 318, 1744–1748. [Google Scholar] [CrossRef]
  23. Isakoff, S.J.; Engelman, J.A.; Irie, H.Y.; Luo, J.; Brachmann, S.M.; Pearline, R.V.; Cantley, L.C.; Brugge, J.S. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005, 65, 10992–11000. [Google Scholar] [CrossRef] [Green Version]
  24. Bosch, A.; Li, Z.; Bergamaschi, A.; Ellis, H.; Toska, E.; Prat, A.; Tao, J.J.; Spratt, D.E.; Viola-Villegas, N.T.; Castel, P.; et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl. Med. 2015, 7, 283ra51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Tokunaga, E.; Kimura, Y.; Mashino, K.; Oki, E.; Kataoka, A.; Ohno, S.; Morita, M.; Kakeji, Y.; Baba, H.; Maehara, Y. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006, 13, 137–144. [Google Scholar] [CrossRef] [PubMed]
  26. Miller, T.W.; Hennessy, B.T.; Gonzalez-Angulo, A.M.; Fox, E.M.; Mills, G.B.; Chen, H.; Higham, C.; Garcia-Echeverria, C.; Shyr, Y.; Arteaga, C.L. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J. Clin. Investig. 2010, 120, 2406–2413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Hanker, A.B.; Sudhan, D.R.; Arteaga, C.L. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell 2020, 37, 496–513. [Google Scholar] [CrossRef] [PubMed]
  28. Courtney, K.D.; Corcoran, R.B.; Engelman, J.A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 2010, 28, 1075–1083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. De Graffenried, L.A.; Friedrichs, W.E.; Russell, D.H.; Donzis, E.J.; Middleton, A.K.; Silva, J.M.; Roth, R.A.; Hidalgo, M. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin. Cancer Res. 2004, 10, 8059–8067. [Google Scholar] [CrossRef] [Green Version]
  30. Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A., 3rd; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnant, M.; Pritchard, K.I.; Lebrun, F.; et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529. [Google Scholar] [CrossRef] [Green Version]
  31. Bachelot, T.; Bourgier, C.; Cropet, C.; Ray-Coquard, I.; Ferrero, J.M.; Freyer, G.; Abadie-Lacourtoisie, S.; Eymard, J.C.; Debled, M.; Spaeth, D.; et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J. Clin. Oncol. 2012, 30, 2718–2724. [Google Scholar] [CrossRef] [PubMed]
  32. Kornblum, N.; Zhao, F.; Manola, J.; Klein, P.; Ramaswamy, B.; Brufsky, A.; Stella, P.J.; Burnette, B.; Telli, M.; Makower, D.F.; et al. Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102. J. Clin. Oncol. 2018, 36, 1556–1563. [Google Scholar] [CrossRef] [PubMed]
  33. Baselga, J.; Im, S.A.; Iwata, H.; Cortes, J.; De Laurentiis, M.; Jiang, Z.; Arteaga, C.L.; Jonat, W.; Clemons, M.; Ito, Y.; et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 904–916. [Google Scholar] [CrossRef] [PubMed]
  34. Di Leo, A.; Johnston, S.; Lee, K.S.; Ciruelos, E.; Lonning, P.E.; Janni, W.; O’Regan, R.; Mouret-Reynier, M.A.; Kalev, D.; Egle, D.; et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018, 19, 87–100. [Google Scholar] [CrossRef] [PubMed]
  35. Krop, I.E.; Mayer, I.A.; Ganju, V.; Dickler, M.; Johnston, S.; Morales, S.; Yardley, D.A.; Melichar, B.; Forero-Torres, A.; Lee, S.C.; et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016, 17, 811–821. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Andre, F.; Ciruelos, E.; Rubovszky, G.; Campone, M.; Loibl, S.; Rugo, H.S.; Iwata, H.; Conte, P.; Mayer, I.A.; Kaufman, B.; et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med. 2019, 380, 1929–1940. [Google Scholar] [CrossRef]
  37. Mayer, I.A.; Prat, A.; Egle, D.; Blau, S.; Fidalgo, J.A.P.; Gnant, M.; Fasching, P.A.; Colleoni, M.; Wolff, A.C.; Winer, E.P.; et al. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Clin. Cancer Res. 2019, 25, 2975–2987. [Google Scholar] [CrossRef] [Green Version]
  38. Rugo, H.S.; Lerebours, F.; Ciruelos, E.; Drullinsky, P.; Ruiz-Borrego, M.; Neven, P.; Park, Y.H.; Prat, A.; Bachelot, T.; Juric, D.; et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021, 22, 489–498. [Google Scholar] [CrossRef]
  39. Dent, S.; Cortes, J.; Im, Y.H.; Dieras, V.; Harbeck, N.; Krop, I.E.; Wilson, T.R.; Cui, N.; Schimmoller, F.; Hsu, J.Y.; et al. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: The SANDPIPER trial. Ann. Oncol. 2021, 32, 197–207. [Google Scholar] [CrossRef]
  40. Saura, C.; Hlauschek, D.; Oliveira, M.; Zardavas, D.; Jallitsch-Halper, A.; de la Pena, L.; Nuciforo, P.; Ballestrero, A.; Dubsky, P.; Lombard, J.M.; et al. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2019, 20, 1226–1238. [Google Scholar] [CrossRef]
  41. Jones, R.H.; Casbard, A.; Carucci, M.; Cox, C.; Butler, R.; Alchami, F.; Madden, T.A.; Bale, C.; Bezecny, P.; Joffe, J.; et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): A multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020, 21, 345–357. [Google Scholar] [CrossRef]
  42. Turner, N.; Oliveira, M.; Howell, S.; Dalenc, F.; Cortés, J. Capivasertib and Fulvestrant for Patients with Aromatase Inhibitor-Resistant Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results from the Phase III CAPItello-291 Trial. Abstract GS3-04 SABCS. 2022. Available online: https://www.sabcs.org/Search-Results?Search=GS3-04 (accessed on 21 February 2023).
  43. Yardley, D.A.; Noguchi, S.; Pritchard, K.I.; Burris, H.A., 3rd; Baselga, J.; Gnant, M.; Hortobagyi, G.N.; Campone, M.; Pistilli, B.; Piccart, M.; et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv. Ther. 2013, 30, 870–884. [Google Scholar] [CrossRef] [Green Version]
  44. Guichard, S.M.; Curwen, J.; Bihani, T.; D’Cruz, C.M.; Yates, J.W.; Grondine, M.; Howard, Z.; Davies, B.R.; Bigley, G.; Klinowska, T.; et al. AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules. Mol. Cancer Ther. 2015, 14, 2508–2518. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Rodrik-Outmezguine, V.S.; Okaniwa, M.; Yao, Z.; Novotny, C.J.; McWhirter, C.; Banaji, A.; Won, H.; Wong, W.; Berger, M.; de Stanchina, E.; et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 2016, 534, 272–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Burris, H.A., 3rd; Kurkjian, C.D.; Hart, L.; Pant, S.; Murphy, P.B.; Jones, S.F.; Neuwirth, R.; Patel, C.G.; Zohren, F.; Infante, J.R. TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Cancer Chemother. Pharmacol. 2017, 80, 261–273. [Google Scholar] [CrossRef] [PubMed]
  47. Varga, A.; Mita, M.M.; Wu, J.J.; Nemunaitis, J.J.; Cloughesy, T.F.; Mischel, P.S.; Bendell, J.C.; Shih, K.C.; Paz-Ares, L.G.; Mahipal, A. Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors. J. Clin. Oncol. 2013, 31, 2609. [Google Scholar] [CrossRef]
  48. Banerji, U.; Dean, E.J.; Gonzalez, M.; Greystoke, A.P.; Basu, B.; Krebs, M.; Puglisi, M.; Grinsted, L.; Oelmann, E.; Burke, W. First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors. J. Clin. Oncol. 2012, 30, 3004. [Google Scholar] [CrossRef]
  49. Akinleye, A.; Avvaru, P.; Furqan, M.; Song, Y.; Liu, D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J. Hematol. Oncol. 2013, 6, 88. [Google Scholar] [CrossRef] [Green Version]
  50. Zhao, J.J.; Cheng, H.; Jia, S.; Wang, L.; Gjoerup, O.V.; Mikami, A.; Roberts, T.M. The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc. Natl. Acad. Sci. USA 2006, 103, 16296–16300. [Google Scholar] [CrossRef] [Green Version]
  51. Mayer, I.A.; Abramson, V.G.; Formisano, L.; Balko, J.M.; Estrada, M.V.; Sanders, M.E.; Juric, D.; Solit, D.; Berger, M.F.; Won, H.H.; et al. A Phase Ib Study of Alpelisib (BYL719), a PI3Kalpha-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin. Cancer Res. 2017, 23, 26–34. [Google Scholar] [CrossRef] [Green Version]
  52. Juric, D.; Janku, F.; Rodon, J.; Burris, H.A.; Mayer, I.A.; Schuler, M.; Seggewiss-Bernhardt, R.; Gil-Martin, M.; Middleton, M.R.; Baselga, J.; et al. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2019, 5, e184475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Engelman, J.A. Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat. Rev. Cancer 2009, 9, 550–562. [Google Scholar] [CrossRef] [PubMed]
  54. Serra, V.; Markman, B.; Scaltriti, M.; Eichhorn, P.J.; Valero, V.; Guzman, M.; Botero, M.L.; Llonch, E.; Atzori, F.; Di Cosimo, S.; et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008, 68, 8022–8030. [Google Scholar] [CrossRef] [Green Version]
  55. Wander, S.A.; Hennessy, B.T.; Slingerland, J.M. Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy. J. Clin. Investig. 2011, 121, 1231–1241. [Google Scholar] [CrossRef] [Green Version]
  56. Layman, R.; Wesolowski, R.; Han, H.; Specht, J.M.; Stringer-Reasor, E.M.; Dees, E.C.; Kabos, P.; Mayer, I.A.; Vaishampayan, U.; Lu, J. Abstract PD13-02: Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer. Cancer Res. 2022, 82, PD13-02. [Google Scholar] [CrossRef]
  57. Dienstmann, R.; Rodon, J.; Serra, V.; Tabernero, J. Picking the point of inhibition: A comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol. Cancer Ther. 2014, 13, 1021–1031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Esposito, A.; Viale, G.; Curigliano, G. Safety, tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: A review. JAMA Oncol. 2019, 5, 1347–1354. [Google Scholar] [CrossRef]
  59. Chia, S.; Gandhi, S.; Joy, A.; Edwards, S.; Gorr, M.; Hopkins, S.; Kondejewski, J.; Ayoub, J.; Califaretti, N.; Rayson, D. Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer. Curr. Oncol. 2015, 22, 33–48. [Google Scholar] [CrossRef] [Green Version]
  60. Bendell, J.C.; Rodon, J.; Burris, H.A.; de Jonge, M.; Verweij, J.; Birle, D.; Demanse, D.; De Buck, S.S.; Ru, Q.C.; Peters, M.; et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 2012, 30, 282–290. [Google Scholar] [CrossRef]
  61. Cheung, L.W.; Hennessy, B.T.; Li, J.; Yu, S.; Myers, A.P.; Djordjevic, B.; Lu, Y.; Stemke-Hale, K.; Dyer, M.D.; Zhang, F.; et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011, 1, 170–185. [Google Scholar] [CrossRef] [Green Version]
  62. Peyton, J.D.; Ahnert, J.R.; Burris, H.; Britten, C.; Chen, L.C.; Tabernero, J.; Duval, V.; Rouyrre, N.; Silva, A.P.; Quadt, C.; et al. A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors. J. Clin. Oncol. 2011, 29, 3066. [Google Scholar] [CrossRef]
  63. Wagner, A.J.; Bendell, J.C.; Dolly, S.; Morgan, J.A.; Ware, J.A.; Fredrickson, J.; Mazina, K.E.; Lauchle, J.O.; Burris, H.A.; Bono, J.S.D. A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors. J. Clin. Oncol. 2011, 29, 3020. [Google Scholar] [CrossRef]
  64. Hoff, D.D.V.; LoRusso, P.; Demetri, G.D.; Weiss, G.J.; Shapiro, G.; Ramanathan, R.K.; Ware, J.A.; Raja, R.; Jin, J.; Levy, G.G.; et al. A phase I dose-escalation study to evaluate GDC-0941, a pan-PI3K inhibitor, administered QD or BID in patients with advanced or metastatic solid tumors. J. Clin. Oncol. 2011, 29, 3052. [Google Scholar] [CrossRef]
  65. Ogita, S.; Lorusso, P. Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. Target Oncol. 2011, 6, 103–117. [Google Scholar] [CrossRef] [PubMed]
  66. Sun, Y.; Dey, P.; Wu, H.; Leyland-Jones, B. P110 α-specific inhibitor is more suitable in PIK3CA mutated breast cancer model but ineffective in PTEN loss of function breast cancer model. Cancer Res. 2012, 72, 2227. [Google Scholar] [CrossRef]
  67. Huang, A.; Fritsch, C.; Wilson, C.; Reddy, A.; Liu, M.; Lehar, J.; Quadt, C.; Hofmann, F.; Schlegel, R. Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel. Cancer Res. 2012, 72, 3749. [Google Scholar] [CrossRef]
  68. Sangai, T.; Akcakanat, A.; Chen, H.; Tarco, E.; Wu, Y.; Do, K.-A.; Miller, T.W.; Arteaga, C.L.; Mills, G.B.; Gonzalez-Angulo, A.M. Biomarkers of Response to Akt Inhibitor MK-2206 in Breast CancerAntitumor Activity of MK-2206. Clin. Cancer Res. 2012, 18, 5816–5828. [Google Scholar] [CrossRef] [Green Version]
  69. Davies, B.R.; Greenwood, H.; Dudley, P.; Crafter, C.; Yu, D.H.; Zhang, J.; Li, J.; Gao, B.; Ji, Q.; Maynard, J.; et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: Pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 2012, 11, 873–887. [Google Scholar] [CrossRef] [Green Version]
  70. Lin, J.; Sampath, D.; Nannini, M.A.; Lee, B.B.; Degtyarev, M.; Oeh, J.; Savage, H.; Guan, Z.; Hong, R.; Kassees, R. Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor ModelsGDC-0068, a Novel Selective ATP-Competitive Akt Inhibitor. Clin. Cancer Res. 2013, 19, 1760–1772. [Google Scholar] [CrossRef] [Green Version]
  71. Costa, C.; Bosch, A. The Strategy of PIKing a Target: What Is AKTually Most Effective? Clin. Cancer Res. 2018, 24, 2029–2031. [Google Scholar] [CrossRef] [Green Version]
  72. Sommer, E.M.; Dry, H.; Cross, D.; Guichard, S.; Davies, B.R.; Alessi, D.R. Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochem. J. 2013, 452, 499–508. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Castel, P.; Ellis, H.; Bago, R.; Toska, E.; Razavi, P.; Carmona, F.J.; Kannan, S.; Verma, C.S.; Dickler, M.; Chandarlapaty, S. PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition. Cancer Cell 2016, 30, 229–242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Gris-Oliver, A.; Palafox, M.; Monserrat, L.; Brasó-Maristany, F.; Òdena, A.; Sánchez-Guixé, M.; Ibrahim, Y.H.; Villacampa, G.; Grueso, J.; Parés, M. Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived XenograftsBiomarkers of Sensitivity to AKT Inhibition in Breast Cancer. Clin. Cancer Res. 2020, 26, 3720–3731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Alves, C.L.; Ehmsen, S.; Terp, M.G.; Portman, N.; Tuttolomondo, M.; Gammelgaard, O.L.; Hundebol, M.F.; Kaminska, K.; Johansen, L.E.; Bak, M.; et al. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer. Nat. Commun. 2021, 12, 5112. [Google Scholar] [CrossRef]
  76. Hyman, D.M.; Smyth, L.M.; Donoghue, M.T.; Westin, S.N.; Bedard, P.L.; Dean, E.J.; Bando, H.; El-Khoueiry, A.B.; Pérez-Fidalgo, J.A.; Mita, A. AKT inhibition in solid tumors with AKT1 mutations. J. Clin. Oncol. 2017, 35, 2251. [Google Scholar] [CrossRef]
  77. Ebi, H.; Costa, C.; Faber, A.C.; Nishtala, M.; Kotani, H.; Juric, D.; Della Pelle, P.; Song, Y.; Yano, S.; Mino-Kenudson, M. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc. Natl. Acad. Sci. USA 2013, 110, 21124–21129. [Google Scholar] [CrossRef] [Green Version]
  78. Vasudevan, K.M.; Barbie, D.A.; Davies, M.A.; Rabinovsky, R.; McNear, C.J.; Kim, J.J.; Hennessy, B.T.; Tseng, H.; Pochanard, P.; Kim, S.Y. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009, 16, 21–32. [Google Scholar] [CrossRef] [Green Version]
  79. Kim, S.-B.; Dent, R.; Im, S.-A.; Espié, M.; Blau, S.; Tan, A.R.; Isakoff, S.J.; Oliveira, M.; Saura, C.; Wongchenko, M.J. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017, 18, 1360–1372. [Google Scholar] [CrossRef]
  80. Schmid, P.; Abraham, J.; Chan, S.; Wheatley, D.; Brunt, M.; Nemsadze, G.; Baird, R.; Park, Y.H.; Hall, P.; Perren, T. AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial. J. Clin. Oncol. 2018, 36, 1007. [Google Scholar] [CrossRef]
  81. Martín, M.; Chan, A.; Dirix, L.; O’Shaughnessy, J.; Hegg, R.; Manikhas, A.; Shtivelband, M.; Krivorotko, P.; López, N.B.; Campone, M. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2–advanced breast cancer (BELLE-4). Ann. Oncol. 2017, 28, 313–320. [Google Scholar] [CrossRef]
  82. Hurvitz, S.A.; Andre, F.; Jiang, Z.; Shao, Z.; Mano, M.S.; Neciosup, S.P.; Tseng, L.-M.; Zhang, Q.; Shen, K.; Liu, D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015, 16, 816–829. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Hsieh, A.C.; Liu, Y.; Edlind, M.P.; Ingolia, N.T.; Janes, M.R.; Sher, A.; Shi, E.Y.; Stumpf, C.R.; Christensen, C.; Bonham, M.J. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012, 485, 55–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Bhagwat, S.V.; Gokhale, P.C.; Crew, A.P.; Cooke, A.; Yao, Y.; Mantis, C.; Kahler, J.; Workman, J.; Bittner, M.; Dudkin, L. Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from RapamycinPreclinical Profile of Dual mTORC1/2 Inhibitor OSI-027. Mol. Cancer Ther. 2011, 10, 1394–1406. [Google Scholar] [CrossRef] [Green Version]
  85. Guo, Y.; Kwiatkowski, D.J. Equivalent Benefit of Rapamycin and a Potent mTOR ATP-Competitive Inhibitor, MLN0128 (INK128), in a Mouse Model of Tuberous SclerosisComparison of Rapamycin and MLN0128 in a TSC Model. Mol. Cancer Res. 2013, 11, 467–473. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Chandarlapaty, S.; Sawai, A.; Scaltriti, M.; Rodrik-Outmezguine, V.; Grbovic-Huezo, O.; Serra, V.; Majumder, P.K.; Baselga, J.; Rosen, N. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011, 19, 58–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Im, S.-A.; Lu, Y.-S.; Bardia, A.; Harbeck, N.; Colleoni, M.; Franke, F.; Chow, L.; Sohn, J.; Lee, K.-S.; Campos-Gomez, S. Overall survival with ribociclib plus endocrine therapy in breast cancer. N. Engl. J. Med. 2019, 381, 307–316. [Google Scholar] [CrossRef] [PubMed]
  88. Finn, R.; Martin, M.; Rugo, H.; Jones, S.; Im, S.; Gelmon, K.; Harbeck, N.; Lipatov, O.; Walshe, J.; Moulder, S. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 2016, 375, 1925–1936. [Google Scholar] [CrossRef]
  89. Cristofanilli, M.; Turner, N.; Bondarenko, I.; Ro, J.; Im, S.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016, 17, 425–439. [Google Scholar]
  90. Hortobagyi, G.; Stemmer, S.; Burris, H.; Yap, Y.; Sonke, G.; Paluch-Shimon, S.; Campone, M.; Petrakova, K.; Blackwell, K.; Winer, E. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann. Oncol. 2018, 29, 1541–1547. [Google Scholar] [CrossRef]
  91. Slamon, D.; Neven, P.; Chia, S.; Fasching, P.; De Laurentiis, M.; Im, S.; Petrakova, K.; Bianchi, G.; Esteva, F.; Martin, M. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J. Clin. Oncol. 2018, 36, 2465–2472. [Google Scholar] [CrossRef]
  92. Sledge, G.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Kaufman, P. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 2017, 35, 2875–2884. [Google Scholar] [CrossRef] [PubMed]
  93. Goetz, M.; Toi, M.; Campone, M.; Sohn, J.; Paluch-Shimon, S.; Huober, J.; Park, I.; Tredan, O.; Chen, S.; Manso, L. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 2017, 35, 3638–3646. [Google Scholar] [CrossRef] [PubMed]
  94. O’Brien, N.A.; McDermott, M.S.; Conklin, D.; Luo, T.; Ayala, R.; Salgar, S.; Chau, K.; DiTomaso, E.; Babbar, N.; Su, F. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer. Breast Cancer Res. 2020, 22, 1–17. [Google Scholar] [CrossRef] [PubMed]
  95. Herrera-Abreu, M.T.; Palafox, M.; Asghar, U.; Rivas, M.A.; Cutts, R.J.; Garcia-Murillas, I.; Pearson, A.; Guzman, M.; Rodriguez, O.; Grueso, J. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast CancerEarly Adaption and Acquired Palbociclib Resistance. Cancer Res. 2016, 76, 2301–2313. [Google Scholar] [CrossRef] [Green Version]
  96. Jansen, V.M.; Bhola, N.E.; Bauer, J.A.; Formisano, L.; Lee, K.M.; Hutchinson, K.E.; Witkiewicz, A.K.; Moore, P.D.; Estrada, M.V.; Sánchez, V.; et al. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer. Cancer Res 2017, 77, 2488–2499. [Google Scholar] [CrossRef] [Green Version]
  97. Clark, A.S.; Makhlin, I.; DeMichele, A. Setting the Pick: Can PI3K Inhibitors Circumvent CDK4/6 Inhibitor Resistance? PI3K Inhibitors+/− CDK 4/6 Inhibitors in Breast Cancer. Clin. Cancer Res. 2021, 27, 371–373. [Google Scholar] [CrossRef]
  98. Garrido-Castro, A.C.; Goel, S. CDK4/6 inhibition in breast cancer: Mechanisms of response and treatment failure. Curr. Breast Cancer Rep. 2017, 9, 26–33. [Google Scholar] [CrossRef] [Green Version]
  99. Makhlin, I.; DeMichele, A. On the rise of cyclin-dependent kinase inhibitors in breast cancer: Progress and ongoing challenges. Future Med. 2020, 9, BMT37. [Google Scholar] [CrossRef]
  100. Vora, S.R.; Juric, D.; Kim, N.; Mino-Kenudson, M.; Huynh, T.; Costa, C.; Lockerman, E.L.; Pollack, S.F.; Liu, M.; Li, X. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014, 26, 136–149. [Google Scholar] [CrossRef] [Green Version]
  101. Pascual, J.; Lim, J.S.; Macpherson, I.R.; Armstrong, A.C.; Ring, A.; Okines, A.F.; Cutts, R.J.; Herrera-Abreu, M.T.; Garcia-Murillas, I.; Pearson, A. Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid CancersTriplet Therapy of Palbociclib, Taselisib, and Fulvestrant. Cancer Discov. 2021, 11, 92–107. [Google Scholar] [CrossRef]
  102. Karimi, L.; Alves, C.L.; Terp, M.G.; Tuttolomondo, M.; Ditzel, H.J. Triple combination targeting ER, CDK4/6, and PI3K inhibits tumor growth in ER+ breast cancer resistant to combined fulvestrant and CDK4/6 or PI3K inhibitor. Cancer Res. 2021, 81, 1415. [Google Scholar] [CrossRef]
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Figure 1. Schematic representation of the PI3K/AKT/mTOR pathway and its targetable regulators. RTK activation stimulates PI3K to convert PIP2 to PIP3, which recruits PDK1, AKT and mTORC2 to the plasma membrane. Both PDK1 and mTORC2 activate AKT, which activates mTORC1. A negative feedback loop is induced by mTORC1 at IRS1. The negative regulator PTEN converts PIP3 back to PIP2. GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase; IRS1, insulin receptor substrate 1; PDK1, phosphoinositide-dependent kinase 1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate.
Figure 1. Schematic representation of the PI3K/AKT/mTOR pathway and its targetable regulators. RTK activation stimulates PI3K to convert PIP2 to PIP3, which recruits PDK1, AKT and mTORC2 to the plasma membrane. Both PDK1 and mTORC2 activate AKT, which activates mTORC1. A negative feedback loop is induced by mTORC1 at IRS1. The negative regulator PTEN converts PIP3 back to PIP2. GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase; IRS1, insulin receptor substrate 1; PDK1, phosphoinositide-dependent kinase 1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate.
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Figure 2. Crosstalk between the PI3K/AKT/mTOR and estrogen receptor pathways in ER+ breast cancer. The ER and PI3K/AKT/mTOR pathways interact directly and indirectly at multiple nodes of each pathway. E2, estrogen; ER, estrogen receptor; ERE, estrogen response elements; RTK, receptor tyrosine kinase.
Figure 2. Crosstalk between the PI3K/AKT/mTOR and estrogen receptor pathways in ER+ breast cancer. The ER and PI3K/AKT/mTOR pathways interact directly and indirectly at multiple nodes of each pathway. E2, estrogen; ER, estrogen receptor; ERE, estrogen response elements; RTK, receptor tyrosine kinase.
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Figure 3. The convergence of the PI3K/AKT/mTOR, cyclin D-CDK4/6-RB and estrogen receptor pathways in ER+ breast cancer. Cyclin D1 functions as a common node by regulating the cell cycle through binding to CDK4/6, inducing ligand-independent activation of ER that can conversely induce cyclin D1 expression, which is further upregulated and stabilized by downstream effectors of the PI3K/AKT/mTOR pathway. Drugs targeting various regulators of the three pathways are also depicted. E2, estrogen; ER, estrogen receptor; ERE, estrogen response elements; RTK, receptor tyrosine kinase.
Figure 3. The convergence of the PI3K/AKT/mTOR, cyclin D-CDK4/6-RB and estrogen receptor pathways in ER+ breast cancer. Cyclin D1 functions as a common node by regulating the cell cycle through binding to CDK4/6, inducing ligand-independent activation of ER that can conversely induce cyclin D1 expression, which is further upregulated and stabilized by downstream effectors of the PI3K/AKT/mTOR pathway. Drugs targeting various regulators of the three pathways are also depicted. E2, estrogen; ER, estrogen receptor; ERE, estrogen response elements; RTK, receptor tyrosine kinase.
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Table
Table 1. Selected clinical trials with PI3K/AKT/mTOR inhibitors in ER+/HER2− advanced breast cancer.
Table 1. Selected clinical trials with PI3K/AKT/mTOR inhibitors in ER+/HER2− advanced breast cancer.
TargetDrugClinical Trial (Phase)Patient PopulationRegimenOutcomeFDA/EMA ApprovalReference
mTORC1EverolimusBOLERO-2 (III)ER+/HER2− mBC
after AI, n = 724		Exemestane ± everolimusmPFS 6.9 vs. 2.8 months,
HR 0.38, p < 0.001		Yes[30]
TAMRAD (II)ER+/HER2− mBC
after AI, n = 111		Tamoxifen ± everolimus6-month CBR 61% vs. 42%;
TTP 8.6 vs. 4.5 months		No[31]
PrE0102 (II)ER+/HER2− mBC
after AI, n = 131		Fulvestrant ± everolimusmPFS 10.3 vs. 5.1,
HR 0.61, p = 0.02		No[32]
Pan-PI3K BuparlisibBELLE-2 (III)ER+/HER2− locally aBC or mBC
after AI, n = 1147		Fulvestrant ± buparlisibmPFS 6.9 vs. 5.0 months, p < 0.001; PIK3CA-mut mPFS 7 vs. 3.2 months, HR 0.56, p < 0.001No[33]
BELLE-3 (II)ER+/HER2− locally aBC or mBC after ET + everolimus n = 432Fulvestrant ± buparlisibmPFS 3.9 vs. 1.8 months,
HR 0.67, p = 000030		No[34]
Pictilisib FERGI (II)ER+/HER2− mBC
Al-resistant
n = 229		Fulvestrant ± pictilisibmPFS 6.6 vs. 5.1 months, HR 0.74, p = 0.096No[35]
Isoform-specific PI3K AlpelisibSOLAR-1 (III)ER+/HER2− mBC
after ET, n = 572		Fulvestrant ± alpelisibPIK3CA-mut mPFS 11.0 vs. 5.7 months, HR 0.65, p < 0.001Yes[36]
NEO-ORB (II)ER+/HER2−
localized BC
neoadjuvant n = 257		Letrozole ± alpelisibORR PIK3CA-mutant, 43% vs. 45%, p = 0.435, PIK3CA-wt, 63% vs. 61%, p = 0.611. No significant differences in pCR.No[37]
BYLIEVE (II)PIK3CA-mut ER+/HER2− mBC
after CDK4/6i
n = 127 (cohort A)		ET ± alpelisibMedian follow-up 11.7 months; pts without disease progression at 6 months: 50.4%No[38]
TaselisibSANDPIPER (III)PIK3CA-mut ER+/HER2− locally aBC or mBC
after AI n = 516		Fulvestrant ± taselisibmPFS 7.4 vs. 5.4 months,
HR 0.70, p = 0.0037		No[39]
LORELEI (II)ER+/HER2−
localized BC
neoadjuvant n = 334		Letrozole ± taselisibOR 39% vs. 50%; OR 1.55; p = 0.049; PIK3CA-mut OR 38% vs. 56%; OR 2.03, p = 0.033. No significant differences in pCR.No[40]
Pan-AKT capivasertibFAKTION (II)ER+/HER2 locally advanced or mBC after AI n = 140Fulvestrant ± capivasertibmPFS 10.3 vs. 4.8 months,
HR 0.58, p = 0.0044;
mOS 29.3 vs. 23.4 months,
HR 0.66, p = 0.035		No[41]
CAPItello-291 (III)ER+/HER2− locally advanced or mBC, after ET ± CDK4/6i
n = 708		Fulvestrant ± capivasertibmPFS 7.2 vs. 3.6 months, p < 0.001;
AKT-altered mPFS 7.3 vs. 3.1 months, p < 0.001		No [42]
aBC, advanced breast cancer; AI, aromatase inhibitors; CDK4/6i, CDK4/6 inhibitors; CBR, clinical benefit rate; ET, endocrine therapy; HR, hazard ratio; mBC, metastatic breast cancer; mPFS, median progression-free survival; mOS, median overall survival; ORR, overall response rate; pCR, pathologic complete response; wt, wild-type.
Table
Table 2. Clinical trials testing triple and sequential double combinations with inhibitors of the PI3K/AKT/mTOR, cyclin D/CDK4/6-RB and ER pathways in ER+ advanced breast cancer.
Table 2. Clinical trials testing triple and sequential double combinations with inhibitors of the PI3K/AKT/mTOR, cyclin D/CDK4/6-RB and ER pathways in ER+ advanced breast cancer.
Target Drugs and RegimenClinical Trial (Phase)Patient Population
(Actual or Estimated)		Outcome
mTORC1everolimus (mTORi) +
ribociclib (CDK4/6i) +
exemestane (AI)		NCT02732119/TRINITI-1 (I/II)ER+/HER2− mBC
after CDK4/6i
n = 104		CBR at week 24: 41.1%
everolimus (mTORi) +
palbociclib (CDK4/6i) +
exemestane (AI)		NCT02871791 (I/II)ER+/HER2− mBC
n = 41		CBR at week 24: 18.8%
PI3K taselisib (isPI3Ki)/pictilisib (pPI3Ki) +
Ppalbociclib (CDK4/6i) +
fulvestrant (SERD) 		NCT02389842/PIPA (Ib)ER+/HER2− mBC
n = 25		ORR 37.5%
CBR 58.3%
mPFS 7.2 months
fulvestrant (SERD) +
ribociclib (CDK4/6i) ±
alpelisib (isPI3Ki) or buparlisib (pPI3Ki)		NCT02088684 (I)ER+/HER2− mBC
n = 70		mPFS 7.2/11.0
vs. 7.2/11.0
fulvestrant (SERD) +
alpelisib (isPI3Ki) or
ribociclib (CDK4/6i)		NCT05625087/SAFIR 03 (II)ER+/HER2− mBC
PIK3CA-mutated
n = 162		NA
letrozole (AI) +
alpelisib (isPI3Ki) or ribociclib (CDK4/6i) ±
ribociclib (CDK4/6i) or alpelisib (isPI3Ki)		NCT01872260 (Ib/II)ER+/HER2−
locally advanced or mBC
n = 255		NA
First-line
letrozole (AI) + ribociclib (CDK4/6i)
Second-line
fulvestrant (SERD) + alpelisib (isPI3K)		NCT03439046/BioItaLEE (III)ER+/HER2− mBC
n = 287		NA
inavolisib (isPI3Ki) +
letrozole (AI) or fulvestrant (SERD) ±
palbociclib (CDK4/6i) 		NCT03006172 (I)ER+/HER2− locally advanced
or mBC, PIK3CA-mutated
n = 256		NA
OP-1250 (CERAN) +
alpelisib (isPI3Ki) or ribociclib (CDK4/6i)		NCT05508906 (Ib)ER+/HER2− mBC NA
CYH33 (isPI3Ki) +
fulvestrant (SERD) or letrozole (AI) ±
palbociclib (CDK4/6i)		NCT04856371 (Ib)ER+/HER2− mBC
PIK3CA-mut
n = 228		NA
AKTfulvestrant (SERD) +
palbociclib (CDK4/6i) ±
capivasertib (AKTi)		NCT04862663/CApitello-292 (Ib/III)ER+/HER2− locally advanced
or mBC after ET
n = 700		NA
fulvestrant (SERD) +
palbociclib (CDK4/6i) ±
ipatasertib (AKTi)		NCT04920708/FAIM (II)ER+/HER2− mBC
with/without ctDNA suppression
n = 324		NA
PI3K/mTORfulvestrant (SERD) +
palbociclib (CDK4/6i) ±
gedatolisib (dual PI3K/mTORi) or
alpelisib (isPI3Ki)		NCT05501886/VIKTORIA-1 (III)ER+/HER2− locally advanced
or mBC after CDK4/6i and AI
with/without PIK3CA mutation
n = 701		NA
AZD2014 (dual PI3K/mTORi) +
fulvestrant (SERD) +
palbociclib (CDK4/6i) 		NCT02599714/PASTOR (I)ER+/HER2−
locally advanced or mBC		NA
AI, aromatase inhibitors; CBR, clinical benefit rate; CDK4/6i, CDK4/6 inhibitor; CERAN, complete estrogen receptor antagonist; ET, endocrine therapy; isPI3Ki, isoform-specific PI3K inhibitor; mBC, metastatic breast cancer; mPFS, median progression-free survival; NA, not available; ORR, objective response rate; pPI3Ki, pan-PI3K inhibitor; SERD, selective estrogen receptor downregulator.
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Alves, C.L.; Ditzel, H.J. Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. Int. J. Mol. Sci. 2023, 24, 4522. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054522

AMA Style

Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. International Journal of Molecular Sciences. 2023; 24(5):4522. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054522

Chicago/Turabian Style

Alves, Carla L., and Henrik J. Ditzel. 2023. "Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer" International Journal of Molecular Sciences 24, no. 5: 4522. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054522

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