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Targeted Cancer Therapy and Mechanisms of Resistance

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 53065

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Special Issue Editor

Prof. Dr. Valentina De Falco

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Istituto di Endocrinologia e Oncologia Sperimentale del CNR, Dipartimento di Medicina Molecolare e Biotecnologie mediche, Università degli Studi di Napoli Federico II, Via Pansini 5, 80131 Napoli, Italy
Interests: cancer; kinase inhibitor; target therapy; signal transduction; cell cycle; mitogenesis; survival; resistance
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Dear Colleagues,

Tumor cells commonly exhibit dependence on a single (often the initiating) activated oncogenic pathway or protein to maintain their malignant proliferation and survival, a phenomenon that is called “oncogene addiction”. According to this concept, protein kinases have been elected as promising molecular targets for cancer therapy. There are several possibilities to target these proteins in cancer, including monoclonal antibodies that can bind to the extracellular domain of the RTK, compounds able to favor the proteolytic degradation of the kinase and, finally, small molecule protein kinase inhibitors (PKIs). In addition to targeting oncogenes, new anticancer treatments have been increasingly developed towards tumor suppressor genes and RNA interference.

Despite promising results in cancer treatment with targeted cancer drugs, clinical experience has shown that only a fraction of patients respond to targeted therapies, even if their tumor expresses the altered target. This kind of resistance is known as primary resistance. Moreover, secondary or acquired resistance to the treatment arises almost invariably when tumors are treated with cancer drugs. Acquired resistance mechanisms can be divided into two main categories: 1) target-dependent and 2) target-independent mechanisms.

Target-dependent resistance typically occurs through genetic modifications of the target. Such genetic modifications may include point mutations and copy number amplifications. The acquisition of mutations conferring drug resistance has been documented for several PKIs, such as drugs against BCR/ABL, EGFR, FLT3, KIT and PDGFR. Evidence suggests mutation may pre-exist in a minority of cancer cells, and it is then selected upon treatment. This suggests that secondary PKI that can also bind the mutated kinase can be used to overcome resistance. Gene amplification is another major mechanism of target-dependent resistance. The selective pressure of the drug can drive amplification of the target gene, thus leading to additional overexpression of the encoded protein.

Instead, target-independent mechanisms occur through activation of alternative pathways that allow the bypass of the drug-mediated block. In other words, cancer cells escape treatment by switching to an alternative signaling pathway that is not inhibited by the drug.

Other mechanisms of resistance can exploit the enormous genome plasticity of cancer cells by modulating miRNA expression or remodeling chromatin. Finally, though not as commonly as with classical cytotoxic drugs, other resistance mechanisms can cause a decrease of the effective intracellular concentration of the targeted cancer drug.

Prof. Dr. Valentina De Falco
Guest Editor

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Keywords

cancer
kinase inhibitors
animal model
cell culture
drug resistance
signal transduction
survival
cell reprogramming
pathways
clinical trials
target therapy
cancer heterogeneity
stem cells
immunity
cell cycle
cell death inhibiting
survival
biomarkers

Related Special Issue

Targeted Cancer Therapy and Mechanisms of Resistance 2.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (14 papers)

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Research

Jump to: Review

21 pages, 8215 KiB

Open AccessArticle

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

by Tingting Shi, Hisakazu Iwama, Koji Fujita, Hideki Kobara, Noriko Nishiyama, Shintaro Fujihara, Yasuhiro Goda, Hirohito Yoneyama, Asahiro Morishita, Joji Tani, Mari Yamada, Mai Nakahara, Kei Takuma and Tsutomu Masaki

Int. J. Mol. Sci. 2021, 22(23), 13071; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313071 - 02 Dec 2021

Cited by 15 | Viewed by 4064

Abstract

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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27 pages, 5186 KiB

Open AccessArticle

Personalised Medicine for Colorectal Cancer Using Mechanism-Based Machine Learning Models

by Annabelle Nwaokorie and Dirk Fey

Int. J. Mol. Sci. 2021, 22(18), 9970; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189970 - 15 Sep 2021

Cited by 6 | Viewed by 5854

Abstract

Gaining insight into the mechanisms of signal transduction networks (STNs) by using critical features from patient-specific mathematical models can improve patient stratification and help to identify potential drug targets. To achieve this, these models should focus on the critical STNs for each cancer, include prognostic genes and proteins, and correctly predict patient-specific differences in STN activity. Focussing on colorectal cancer and the WNT STN, we used mechanism-based machine learning models to identify genes and proteins with significant associations to event-free patient survival and predictive power for explaining patient-specific differences of STN activity. First, we identified the WNT pathway as the most significant pathway associated with event-free survival. Second, we built linear-regression models that incorporated both genes and proteins from established mechanistic models in the literature and novel genes with significant associations to event-free patient survival. Data from The Cancer Genome Atlas and Clinical Proteomic Tumour Analysis Consortium were used, and patient-specific STN activity scores were computed using PROGENy. Three linear regression models were built, based on; (1) the gene-set of a state-of-the-art mechanistic model in the literature, (2) novel genes identified, and (3) novel proteins identified. The novel genes and proteins were genes and proteins of the extant WNT pathway whose expression was significantly associated with event-free survival. The results show that the predictive power of a model that incorporated novel event-free associated genes is better compared to a model focussing on the genes of a current state-of-the-art mechanistic model. Several significant genes that should be integrated into future mechanistic models of the WNT pathway are DVL3, FZD5, RAC1, ROCK2, GSK3B, CTB2, CBT1, and PRKCA. Thus, the study demonstrates that using mechanistic information in combination with machine learning can identify novel features (genes and proteins) that are important for explaining the STN heterogeneity between patients and their association to clinical outcomes. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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21 pages, 4253 KiB

Open AccessArticle

Activated ERK Signaling Is One of the Major Hub Signals Related to the Acquisition of Radiotherapy-Resistant MDA-MB-231 Breast Cancer Cells

by Anjugam Paramanantham, Eun Joo Jung, Se-IL Go, Bae Kwon Jeong, Jin-Myung Jung, Soon Chan Hong, Gon Sup Kim and Won Sup Lee

Int. J. Mol. Sci. 2021, 22(9), 4940; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094940 - 06 May 2021

Cited by 10 | Viewed by 3300

Abstract

Breast cancer is one of the major causes of deaths due to cancer, especially in women. The crucial barrier for breast cancer treatment is resistance to radiation therapy, one of the important local regional therapies. We previously established and characterized radio-resistant MDA-MB-231 breast cancer cells (RT-R-MDA-MB-231 cells) that harbor a high expression of cancer stem cells (CSCs) and the EMT phenotype. In this study, we performed antibody array analysis to identify the hub signaling mechanism for the radiation resistance of RT-R-MDA-MB-231 cells by comparing parental MDA-MB-231 (p-MDA-MB-231) and RT-R-MDA-MB-231 cells. Antibody array analysis unveiled that the MAPK1 protein was the most upregulated protein in RT-R-MDA-MB-231 cells compared to in p-MDA-MB-231 cells. The pathway enrichment analysis also revealed the presence of MAPK1 in almost all enriched pathways. Thus, we used an MEK/ERK inhibitor, PD98059, to block the MEK/ERK pathway and to identify the role of MAPK1 in the radio-resistance of RT-R-MDA-MB-231 cells. MEK/ERK inhibition induced cell death in both p-MDA-MB-231 and RT-R-MDA-MB-231 cells, but the death mechanism for each cell was different; p-MDA-MB-231 cells underwent apoptosis, showing cell shrinkage and PARP-1 cleavage, while RT-R-MDA-MB-231 cells underwent necroptosis, showing mitochondrial dissipation, nuclear swelling, and an increase in the expressions of CypA and AIF. In addition, MEK/ERK inhibition reversed the radio-resistance of RT-R-MDA-MB-231 cells and suppressed the increased expression of CSC markers (CD44 and OCT3/4) and the EMT phenotype (β-catenin and N-cadherin/E-cadherin). Taken together, this study suggests that activated ERK signaling is one of the major hub signals related to the radio-resistance of MDA-MB-231 breast cancer cells. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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16 pages, 14513 KiB

Open AccessArticle

Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells

by Tiziana Fioretti, Armando Cevenini, Mariateresa Zanobio, Maddalena Raia, Daniela Sarnataro, Fabio Cattaneo, Rosario Ammendola and Gabriella Esposito

Int. J. Mol. Sci. 2021, 22(9), 4623; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094623 - 28 Apr 2021

Cited by 4 | Viewed by 2041

Abstract

The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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21 pages, 16038 KiB

Open AccessArticle

Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway

by Entaz Bahar, Ji-Ye Kim, Dong-Chul Kim, Hyun-Soo Kim and Hyonok Yoon

Int. J. Mol. Sci. 2021, 22(8), 3916; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083916 - 10 Apr 2021

Cited by 12 | Viewed by 3245

Abstract

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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15 pages, 2898 KiB

Open AccessCommunication

Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model

by Youri Oh, Hoyong Jung, Hyejin Kim, Jihyun Baek, Joonhong Jun, Hyunwook Cho, Daseul Im and Jung-Mi Hah

Int. J. Mol. Sci. 2021, 22(8), 3865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083865 - 08 Apr 2021

Cited by 3 | Viewed by 2031

Abstract

Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Given the hybridized 3D-QSAR models, we designed and synthesized 4-benzyloxy-1-(2-arylaminopyridin-4-yl)-1H-pyrazole-3-carboxamides, and we inspected its inhibitory activities to identify novel PLK1 inhibitors with decent potency and selectivity. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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Graphical abstract

14 pages, 3364 KiB

Open AccessArticle

Transcriptomic Profiles of CD47 in Breast Tumors Predict Outcome and Are Associated with Immune Activation

by María del Mar Noblejas-López, Mariona Baliu-Piqué, Cristina Nieto-Jiménez, Francisco J. Cimas, Esther C. Morafraile, Atanasio Pandiella, Ángel L. Corbi, Balázs Győrffy and Alberto Ocaña

Int. J. Mol. Sci. 2021, 22(8), 3836; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083836 - 07 Apr 2021

Cited by 2 | Viewed by 2215

Abstract

Targeting the innate immune system has attracted attention with the development of anti- CD47 antibodies. Anti-CD47 antibodies block the inhibition of the phagocytic activity of macrophages caused by the up-regulation of CD47 on tumor cells. In this study, public genomic data was used to identify genes highly expressed in breast tumors with elevated CD47 expression and analyzed the association between the presence of tumor immune infiltrates and the expression of the selected genes. We found that 142 genes positively correlated with CD47, of which 83 predicted favorable and 32 detrimental relapse-free survival (RFS). From those associated with favorable RFS, we selected the genes with immunologic biological functions and defined a CD47-immune signature composed of PTPRC, HLA-E, TGFBR2, PTGER4, ETS1, and OPTN. In the basal-like and HER2+ breast cancer subtypes, the expression of the CD47-immune signature predicted favorable outcome, correlated with the presence of tumor immune infiltrates, and with gene expression signatures of T cell activation. Moreover, CD47 up-regulated genes associated with favorable survival correlated with pro-tumoral macrophages. In summary, we described a CD47-immune gene signature composed of 6 genes associated with favorable prognosis, T cell activation, and pro-tumoral macrophages in breast cancer tumors expressing high levels of CD47. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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15 pages, 4426 KiB

Open AccessArticle

Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells

by Chinatsu Kurasaka, Yoko Ogino and Akira Sato

Int. J. Mol. Sci. 2021, 22(6), 2916; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062916 - 13 Mar 2021

Cited by 11 | Viewed by 2462

Abstract

5-Fluorouracil (5-FU) is a cornerstone drug used in the treatment of colorectal cancer (CRC). However, the development of resistance to 5-FU and its analogs remain an unsolved problem in CRC treatment. In this study, we investigated the molecular mechanisms and tumor biological aspects of 5-FU resistance in CRC HCT116 cells. We established an acquired 5-FU-resistant cell line, HCT116R^F10. HCT116R^F10 cells were cross-resistant to the 5-FU analog, fluorodeoxyuridine. In contrast, HCT116R^F10 cells were collaterally sensitive to SN-38 and CDDP compared with the parental HCT16 cells. Whole-exome sequencing revealed that a cluster of genes associated with the 5-FU metabolic pathway were not significantly mutated in HCT116 or HCT116R^F10 cells. Interestingly, HCT116R^F10 cells were regulated by the function of thymidylate synthase (TS), a 5-FU active metabolite 5-fluorodeoxyuridine monophosphate (FdUMP) inhibiting enzyme. Half of the TS was in an active form, whereas the other half was in an inactive form. This finding indicates that 5-FU-resistant cells exhibited increased TS expression, and the TS enzyme is used to trap FdUMP, resulting in resistance to 5-FU and its analogs. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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19 pages, 4210 KiB

Open AccessArticle

HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma

by Sang Wu Lee, Soo-Keun Yeon, Go Woon Kim, Dong Hoon Lee, Yu Hyun Jeon, Jung Yoo, So Yeon Kim and So Hee Kwon

Int. J. Mol. Sci. 2021, 22(3), 1341; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031341 - 29 Jan 2021

Cited by 12 | Viewed by 2616

Abstract

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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13 pages, 2640 KiB

Open AccessArticle

Hyperthermia Induced by Gold Nanoparticles and Visible Light Photothermy Combined with Chemotherapy to Tackle Doxorubicin Sensitive and Resistant Colorectal Tumor 3D Spheroids

by Catarina Roma-Rodrigues, Inês Pombo, Alexandra R. Fernandes and Pedro V. Baptista

Int. J. Mol. Sci. 2020, 21(21), 8017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218017 - 28 Oct 2020

Cited by 20 | Viewed by 3367

Abstract

Current cancer therapies are frequently ineffective and associated with severe side effects and with acquired cancer drug resistance. The development of effective therapies has been hampered by poor correlations between pre-clinical and clinical outcomes. Cancer cell-derived spheroids are three-dimensional (3D) structures that mimic layers of tumors in terms of oxygen and nutrient and drug resistance gradients. Gold nanoparticles (AuNP) are promising therapeutic agents which permit diminishing the emergence of secondary effects and increase therapeutic efficacy. In this work, 3D spheroids of Doxorubicin (Dox)-sensitive and -resistant colorectal carcinoma cell lines (HCT116 and HCT116-DoxR, respectively) were used to infer the potential of the combination of chemotherapy and Au-nanoparticle photothermy in the visible (green laser of 532 nm) to tackle drug resistance in cancer cells. Cell viability analysis of 3D tumor spheroids suggested that AuNPs induce cell death in the deeper layers of spheroids, further potentiated by laser irradiation. The penetration of Dox and earlier spheroid disaggregation is potentiated in combinatorial therapy with Dox, AuNP functionalized with polyethylene glycol (AuNP@PEG) and irradiation. The time point of Dox administration and irradiation showed to be important for spheroids destabilization. In HCT116-sensitive spheroids, pre-irradiation induced earlier disintegration of the 3D structure, while in HCT116 Dox-resistant spheroids, the loss of spheroid stability occurred almost instantly in post-irradiated spheroids, even with lower Dox concentrations. These results point towards the application of new strategies for cancer therapeutics, reducing side effects and resistance acquisition. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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Review

Jump to: Research

23 pages, 6461 KiB

Open AccessReview

Wee1 Kinase: A Potential Target to Overcome Tumor Resistance to Therapy

by Francesca Esposito, Raffaella Giuffrida, Gabriele Raciti, Caterina Puglisi and Stefano Forte

Int. J. Mol. Sci. 2021, 22(19), 10689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910689 - 01 Oct 2021

Cited by 15 | Viewed by 4802

Abstract

During the cell cycle, DNA suffers several lesions that need to be repaired prior to entry into mitosis to preserve genome integrity in daughter cells. Toward this aim, cells have developed complex enzymatic machinery, the so-called DNA damage response (DDR), which is able to repair DNA, temporarily stopping the cell cycle to provide more time to repair, or if the damage is too severe, inducing apoptosis. This DDR mechanism is considered the main source of resistance to DNA-damaging therapeutic treatments in oncology. Recently, cancer stem cells (CSCs), which are a small subset of tumor cells, were identified as tumor-initiating cells. CSCs possess self-renewal potential and persistent tumorigenic capacity, allowing for tumor re-growth and relapse. Compared with cancer cells, CSCs are more resistant to therapeutic treatments. Wee1 is the principal gatekeeper for both G2/M and S-phase checkpoints, where it plays a key role in cell cycle regulation and DNA damage repair. From this perspective, Wee1 inhibition might increase the effectiveness of DNA-damaging treatments, such as radiotherapy, forcing tumor cells and CSCs to enter into mitosis, even with damaged DNA, leading to mitotic catastrophe and subsequent cell death. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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19 pages, 1018 KiB

Open AccessReview

Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer

by Michela Palleschi, Gianluca Tedaldi, Marianna Sirico, Alessandra Virga, Paola Ulivi and Ugo De Giorgi

Int. J. Mol. Sci. 2021, 22(15), 7884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157884 - 23 Jul 2021

Cited by 8 | Viewed by 2406

Abstract

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms “PARP inhibitors” and “breast cancer”, was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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21 pages, 5069 KiB

Open AccessReview

Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma

by Agnieszka Rybarczyk-Kasiuchnicz, Rodryg Ramlau and Katarzyna Stencel

Int. J. Mol. Sci. 2021, 22(2), 593; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020593 - 08 Jan 2021

Cited by 36 | Viewed by 9747

Abstract

Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10–20% of lung adenocarcinomas. Approximately 3–7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs—small-molecule tyrosine kinase inhibitors—has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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Open AccessReview

The Cellular Prion Protein: A Promising Therapeutic Target for Cancer

by Gyeongyun Go and Sang Hun Lee

Int. J. Mol. Sci. 2020, 21(23), 9208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239208 - 02 Dec 2020

Cited by 20 | Viewed by 3466

Abstract

Studies on the cellular prion protein (PrP^C) have been actively conducted because misfolded PrP^C is known to cause transmissible spongiform encephalopathies or prion disease. PrP^C is a glycophosphatidylinositol-anchored cell surface glycoprotein that has been reported to affect several cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also been reported that PrP^C mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrP^C regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrP^C promotes tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In addition, we discuss strategies to treat tumors by modulating the function and expression of PrP^C via the regulation of HSPA1L/HIF-1α expression and using an anti-prion antibody. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy and Mechanisms of Resistance)

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