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Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising...
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Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 130590

Special Issue Editor

Prof. Dr. Patrizia Limonta

E-Mail Website
Guest Editor
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy
Interests: cancer cell biology; mechanisms of cancer cell death; hormone receptors in cancer cells; cancer stem cells; metabolic rewiring in cancer cells; drug resistance; tumor microenvironment, anticancer activity of natural compounds; prostate cancer; melanoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer still represents a major health problem worldwide. Most tumors are diagnosed at an early stage and can be removed by surgical resection. For advanced or inoperable malignancies, treatments include radiation therapy, cytotoxic chemotherapy, targeted therapies, and immunotherapies, depending on the molecular features of the specific tumor. Unfortunately, despite the good initial response, the development of resistance to these approaches continues to represent the leading cause of cancer recurrence and death.

In this context, a better understanding of the molecular mechanisms underlying cancer progression and acquired drug resistance are urgently needed to identify novel therapeutic strategies and to improve clinical outcomes.

In the last years, several biological events have been demonstrated to be involved in the development of resistance to standard therapies: activation of growth factor receptors and their downstream signaling pathways, DNA repair mechanisms, metabolic rewiring, miRNA expression and transfer, ATP-binding cassette transporter-mediated drug extrusion, cancer stem cell subpopulation enrichment. Another key mechanism commonly implicated in the reduction of anticancer drug sensitivity is represented by the bidirectional communication between tumor cells and their microenvironment (stromal cells, vascular endothelial cells, immune cells), often regulated by extracellular vesicles and their molecular cargo. More recently, the crucial role of the gut microbiome in tumor progression and the response to different anticancer agents has also been highlighted.

Several efforts are now directed towards the identification of innovative biomarkers that could predict treatment responses and prevent tumor relapse. Circulating cancer cells, as well as circulating tumor DNA, cancer cell secretome and tumor-derived extracellular vesicles and miRNAs can be easily isolated from patient body fluids. Thus, liquid biopsies are currently considered as an interesting tool not only for cancer detection but also to define or promptly modify the proper antitumor treatment regimens.

Based on current preclinical and clinical findings, various novel therapeutic approaches, involving both synthetic and natural compounds, are being developed to overcome drug resistance.

In this review, we will describe the molecular mechanisms underlying the development of drug resistance in cancer and discuss the new therapeutic strategies aimed at preventing tumor relapse.

Prof. Dr. Patrizia Limonta
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Drug resistance
  • Intracellular signaling mechanisms
  • Metabolic rewiring, epigenetic changes
  • ATP-Binding Cassette transporters
  • Cancer stem cells
  • Tumor microenvironment
  • Extracellular vesicles
  • Liquid biopsies
  • New therapeutic strategies

Published Papers (29 papers)

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Editorial

Jump to: Research, Review

9 pages, 214 KiB  
Editorial
Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression
by Fabrizio Fontana, Martina Anselmi and Patrizia Limonta
Cancers 2022, 14(7), 1614; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071614 - 23 Mar 2022
Cited by 15 | Viewed by 2530
Abstract
Cancer still represents a major global burden, being the second leading cause of death worldwide [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)

Research

Jump to: Editorial, Review

20 pages, 2704 KiB  
Article
Systemic Mobilization of Breast Cancer Resistance Protein in Response to Oncogenic Stress
by Małgorzata Szczygieł, Marcin Markiewicz, Milena Julia Szafraniec, Agnieszka Hojda, Leszek Fiedor and Krystyna Urbanska
Cancers 2022, 14(2), 313; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020313 - 09 Jan 2022
Cited by 4 | Viewed by 1861
Abstract
The breast cancer resistance protein (BCRP or ABCG2) involved in cancer multidrug resistance (MDR), transports many hydrophobic compounds, including a number of anti-cancer drugs. Our comprehensive study using a mouse model reveals that a subcutaneously growing tumor strongly affects the expression of BCRP [...] Read more.
The breast cancer resistance protein (BCRP or ABCG2) involved in cancer multidrug resistance (MDR), transports many hydrophobic compounds, including a number of anti-cancer drugs. Our comprehensive study using a mouse model reveals that a subcutaneously growing tumor strongly affects the expression of BCRP in the host’s normal organs on both the transcriptional and translational level. Additionally, the efflux of BCRP substrates is markedly enhanced. The levels of BCRP and its transcript in normal tissues distant from the tumor site correlate with tumor growth and the levels of cytokines in the peripheral blood. Thus, oncogenic stress causes transient systemic upregulation of BCRP in the host’s normal tissues and organs, which is possibly mediated via cytokines. Because BCRP upregulation takes place in many organs as early as the initial stages of tumor development, it reveals a most basic mechanism that may be responsible for the induction of primary MDR. We hypothesize that such effects are not tumor-specific responses, but rather constitute a more universal defense strategy. The xenobiotic transporters are systemically mobilized due to various stresses, seemingly in a pre-emptive manner so that the body can be quickly and efficiently detoxified. Our findings shed new light on the biology of cancer and on the complexity of cancer–host interactions and are highly relevant to cancer therapies as well as to the design of new generations of therapeutics and personalized medicine. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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18 pages, 3207 KiB  
Article
Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines
by Kathryn M. Appleton, Charuta C. Palsuledesai, Sean A. Misek, Maja Blake, Joseph Zagorski, Kathleen A. Gallo, Thomas S. Dexheimer and Richard R. Neubig
Cancers 2021, 13(9), 2012; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092012 - 22 Apr 2021
Cited by 5 | Viewed by 2584
Abstract
The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAF [...] Read more.
The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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Graphical abstract

21 pages, 5304 KiB  
Article
Targeting the IL-6/STAT3 Signalling Cascade to Reverse Tamoxifen Resistance in Estrogen Receptor Positive Breast Cancer
by Ho Tsoi, Ellen P. S. Man, Ka Man Chau and Ui-Soon Khoo
Cancers 2021, 13(7), 1511; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071511 - 25 Mar 2021
Cited by 22 | Viewed by 2885
Abstract
Breast cancer is the most common female cancer. About 70% of breast cancer patients are estrogen receptor α (ERα) positive (ER+) with tamoxifen being the most commonly used anti-endocrine therapy. However, up to 50% of patients who receive tamoxifen suffer recurrence. We previously [...] Read more.
Breast cancer is the most common female cancer. About 70% of breast cancer patients are estrogen receptor α (ERα) positive (ER+) with tamoxifen being the most commonly used anti-endocrine therapy. However, up to 50% of patients who receive tamoxifen suffer recurrence. We previously identified BQ323636.1 (BQ), a novel splice variant of NCOR2, can robustly predict tamoxifen resistance in ER+ primary breast cancer. Here we show that BQ can enhance IL-6/STAT3 signalling. We demonstrated that through interfering with NCOR2 suppressive activity, BQ favours the binding of ER to IL-6 promoter and the binding of NF-ĸB to IL-6 receptor (IL-6R) promoter, leading to the up-regulation of both IL-6 and IL-6R and thus the activation of STAT3. Knockdown of IL-6R could compromise tamoxifen resistance mediated by BQ. Furthermore, Tocilizumab (TCZ), an antibody that binds to IL-6R, could effectively reverse tamoxifen resistance both in vitro and in vivo. Analysis of clinical breast cancer samples confirmed that IL-6R expression was significantly associated with BQ expression and tamoxifen resistance in primary breast cancer, with high IL-6R expression correlating with poorer survival. Multivariate Cox-regression analysis confirmed that high IL-6R expression remained significantly associated with poor overall as well as disease-specific survival in ER+ breast cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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25 pages, 3338 KiB  
Article
Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1
by Rodrigo G. B. Cruz, Stephen F. Madden, Cathy E. Richards, Sri HariKrishna Vellanki, Hanne Jahns, Lance Hudson, Joanna Fay, Naoimh O’Farrell, Katherine Sheehan, Karin Jirström, Kieran Brennan and Ann M. Hopkins
Cancers 2021, 13(4), 871; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040871 - 19 Feb 2021
Cited by 7 | Viewed by 2923
Abstract
The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional [...] Read more.
The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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15 pages, 3132 KiB  
Article
Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib
by Silvia La Monica, Claudia Fumarola, Daniele Cretella, Mara Bonelli, Roberta Minari, Andrea Cavazzoni, Graziana Digiacomo, Maricla Galetti, Francesco Volta, Maicol Mancini, Pier Giorgio Petronini, Marcello Tiseo and Roberta Alfieri
Cancers 2021, 13(1), 6; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010006 - 22 Dec 2020
Cited by 25 | Viewed by 4008
Abstract
Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation [...] Read more.
Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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Graphical abstract

18 pages, 2621 KiB  
Article
Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib, Gefitinib, Afatinib, Crizotinib, Sorafenib, Sunitinib, and Dasatinib: Implications for Clinical Resistance
by Richard J. Honeywell, Ietje Kathmann, Elisa Giovannetti, Carmelo Tibaldi, Egbert F. Smit, Maria N. Rovithi, Henk M.W. Verheul and Godefridus J. Peters
Cancers 2020, 12(11), 3322; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113322 - 10 Nov 2020
Cited by 11 | Viewed by 2512
Abstract
Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), [...] Read more.
Background: tyrosine kinase inhibitors (TKIs) inhibit phosphorylation of signaling proteins. TKIs often show large variations in the clinic due to poor pharmacology, possibly leading to resistance. We compared gut absorption of inhibitors of epidermal growth factor receptor (erlotinib, gefitinib, and afatinib), ALK-cMET (crizotinib), PDGFR/BCR-Abl (dasatinib), and multikinase inhibitors (sunitinib and sorafenib). In clinical samples, we measured the disposition of each compound within various blood compartments. Methods: we used an optimized CaCo2 gut epithelial model to characterize 20 µM TKI absorption. The apical/basolateral transfer is considered to represent the gut/blood transfer. Drugs were measured using LC-MS/MS. Results: sorafenib and sunitinib showed the highest apical/basolateral transfer (Papp 14.1 and 7.7 × 10−6 cm/s, respectively), followed by dasatinib (3.4), afatinib (1.5), gefitinib (0.38), erlotinib (0.13), and crizotinib (n.d.). However, the net absorptions for dasatinib, afatinib, crizotinib, and erlotinib were highly negative (efflux ratios >5) or neutral/negative, sorafenib (0.86), gefitinib (1.0), and sunitinib (1.6). A high negative absorption may result in resistance because of a poor exposure of tissues to the drug. Accumulation of the TKIs at the end of the transfer period (A->B) was not detectable for erlotinib, very low for afatinib 0.45 pmol/μg protein), followed by gefitinib (0.79), dasatinib (1.1), sorafenib (1.65), and crizotinib (2.11), being highest for sunitinib (11.9). A similar pattern was found for accumulation of these drugs in other colon cell lines, WiDr and HT29. In clinical samples, drugs accumulated consistently in red blood cells; blood to plasma ratios were all >3 (sorafenib) or over 30 for erlotinib. Conclusions: TKIs are consistently poorly absorbed, but accumulation in red blood cells seems to compensate for this. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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20 pages, 3005 KiB  
Article
Comprehensive Analysis of DNA Methylation and Prediction of Response to NeoadjuvantTherapy in Locally Advanced Rectal Cancer
by Luisa Matos do Canto, Mateus Camargo Barros-Filho, Cláudia Aparecida Rainho, Diogo Marinho, Bruna Elisa Catin Kupper, Maria Dirlei Ferreira de Souza Begnami, Cristovam Scapulatempo-Neto, Birgitte Mayland Havelund, Jan Lindebjerg, Fabio Albuquerque Marchi, Jan Baumbach, Samuel Aguiar Jr. and Silvia Regina Rogatto
Cancers 2020, 12(11), 3079; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113079 - 22 Oct 2020
Cited by 12 | Viewed by 2821
Abstract
The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation [...] Read more.
The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to OBSL1, GPR1, and INSIG1 genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cis-regulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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16 pages, 3331 KiB  
Article
HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line
by Hye Jin Lee, Seungho Shin, Jinho Kang, Ki-Cheol Han, Yeul Hong Kim, Jeoung-Won Bae and Kyong Hwa Park
Cancers 2020, 12(9), 2630; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092630 - 15 Sep 2020
Cited by 10 | Viewed by 3067
Abstract
Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets [...] Read more.
Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets that may overcome resistance. Lapatinib-resistant cell lines were established using SKBR3 and BT474 cells. We evaluated cell viability and cell signal changes, gene expression and protein changes. In the xenograft mouse model, anti-tumor effects were evaluated using drugs. Analysis of the protein interaction network in two resistant cell lines with different lapatinib resistance mechanisms showed that HSP90 protein was commonly increased. When Heat Shock Protein 90 (HSP90) inhibitors were administered alone to both resistant cell lines, cell proliferation and protein expression were effectively inhibited. However, inhibition of cell proliferation and protein expression with a combination of lapatinib and HSP90 inhibitors showed a more synergistic effect in the LR-BT474 cell line than the LR-SKBR3 cell line, and the same result was exhibited with the xenograft model. These results suggest that HSP90 inhibitors in patients with lapatinib-resistant Estrogen Receptor (ER) (+) HER2 (+) breast cancer are promising therapeutics for future clinical trials. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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14 pages, 9024 KiB  
Article
Impact of ERCC1, XPF and DNA Polymerase β Expression on Platinum Response in Patient-Derived Ovarian Cancer Xenografts
by Federica Guffanti, Maria Francesca Alvisi, Elisa Caiola, Francesca Ricci, Marcella De Maglie, Sabina Soldati, Monica Ganzinelli, Alessandra Decio, Raffaella Giavazzi, Eliana Rulli and Giovanna Damia
Cancers 2020, 12(9), 2398; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092398 - 24 Aug 2020
Cited by 9 | Viewed by 2560
Abstract
Platinum resistance is an unmet medical need in ovarian carcinoma. Molecular biomarkers to predict the response to platinum-based therapy could allow patient stratification and alternative therapeutic strategies early in clinical management. Sensitivity and resistance to platinum therapy are partially determined by the tumor’s [...] Read more.
Platinum resistance is an unmet medical need in ovarian carcinoma. Molecular biomarkers to predict the response to platinum-based therapy could allow patient stratification and alternative therapeutic strategies early in clinical management. Sensitivity and resistance to platinum therapy are partially determined by the tumor’s intrinsic DNA repair activities, including nucleotide excision repair (NER) and base excision repair (BER). We investigated the role of the NER proteins—ERCC1, XPF, ERCC1/XPF complex—and of the BER protein DNA polymerase β, as possible biomarkers of cisplatin (DDP) response in a platform of recently established patient-derived ovarian carcinoma xenografts (OC-PDXs). ERCC1 and DNA polymerase β protein expressions were measured by immunohistochemistry, the ERCC1/XPF foci number was detected by proximity ligation assay (PLA) and their mRNA levels by real-time PCR. We then correlated the proteins, gene expression and ERCC1/XPF complexes with OC-PDXs’ response to platinum. To the best of our knowledge, this is the first investigation of the role of the ERCC1/XPF complex, detected by PLA, in relation to the response to DDP in ovarian carcinoma. None of the proteins in the BER and NER pathways studied predicted platinum activity in this panel of OC-PDXs, nor did the ERCC1/XPF foci number. These results were partially explained by the experimental evidence that the ERCC1/XPF complex increases after DDP treatment and this possibly better associates with the cancer cells’ abilities to activate the NER pathway to repair platinum-induced damage than its basal level. Our findings highlight the need for DNA functional assays to predict the response to platinum-based therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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Review

Jump to: Editorial, Research

17 pages, 699 KiB  
Review
Breast Cancer Drug Resistance: Overcoming the Challenge by Capitalizing on MicroRNA and Tumor Microenvironment Interplay
by Giulia Cosentino, Ilaria Plantamura, Elda Tagliabue, Marilena V. Iorio and Alessandra Cataldo
Cancers 2021, 13(15), 3691; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153691 - 22 Jul 2021
Cited by 21 | Viewed by 3482
Abstract
The clinical management of breast cancer reaches new frontiers every day. However, the number of drug resistant cases is still high, and, currently, this constitutes one of the major challenges that cancer research has to face. For instance, 50% of women affected with [...] Read more.
The clinical management of breast cancer reaches new frontiers every day. However, the number of drug resistant cases is still high, and, currently, this constitutes one of the major challenges that cancer research has to face. For instance, 50% of women affected with HER2 positive breast cancer presents or acquires resistance to trastuzumab. Moreover, for patients affected with triple negative breast cancer, standard chemotherapy is still the fist-line therapy, and often patients become resistant to treatments. Tumor microenvironment plays a crucial role in this context. Indeed, cancer-associated stromal cells deliver oncogenic cues to the tumor and vice versa to escape exogenous insults. It is well known that microRNAs are among the molecules exploited in this aberrant crosstalk. Indeed, microRNAs play a crucial function both in the induction of pro-tumoral traits in stromal cells and in the stroma-mediated fueling of tumor aggressiveness. Here, we summarize the most recent literature regarding the involvement of miRNAs in the crosstalk between tumor and stromal cells and their capability to modulate tumor microenvironment characteristics. All up-to-date findings suggest that microRNAs in the TME could serve both to reverse malignant phenotype of stromal cells, modulating response to therapy, and as predictive/prognostic biomarkers. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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23 pages, 1856 KiB  
Review
Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies
by Claudia Maria Hattinger, Maria Pia Patrizio, Leonardo Fantoni, Chiara Casotti, Chiara Riganti and Massimo Serra
Cancers 2021, 13(12), 2878; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122878 - 09 Jun 2021
Cited by 55 | Viewed by 4290
Abstract
High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired [...] Read more.
High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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27 pages, 1099 KiB  
Review
MicroRNAs as Epigenetic Determinants of Treatment Response and Potential Therapeutic Targets in Prostate Cancer
by Valentina Doldi, Rihan El Bezawy and Nadia Zaffaroni
Cancers 2021, 13(10), 2380; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102380 - 14 May 2021
Cited by 10 | Viewed by 2814
Abstract
Prostate cancer (PCa) is the second most common tumor in men worldwide, and the fifth leading cause of male cancer-related deaths in western countries. PC is a very heterogeneous disease, meaning that optimal clinical management of individual patients is challenging. Depending on disease [...] Read more.
Prostate cancer (PCa) is the second most common tumor in men worldwide, and the fifth leading cause of male cancer-related deaths in western countries. PC is a very heterogeneous disease, meaning that optimal clinical management of individual patients is challenging. Depending on disease grade and stage, patients can be followed in active surveillance protocols or undergo surgery, radiotherapy, hormonal therapy, and chemotherapy. Although therapeutic advancements exist in both radiatiotherapy and chemotherapy, in a considerable proportion of patients, the treatment remains unsuccessful, mainly due to tumor poor responsiveness and/or recurrence and metastasis. microRNAs (miRNAs), small noncoding RNAs that epigenetically regulate gene expression, are essential actors in multiple tumor-related processes, including apoptosis, cell growth and proliferation, autophagy, epithelial-to-mesenchymal transition, invasion, and metastasis. Given that these processes are deeply involved in cell response to anti-cancer treatments, miRNAs have been considered as key determinants of tumor treatment response. In this review, we provide an overview on main PCa-related miRNAs and describe the biological mechanisms by which specific miRNAs concur to determine PCa response to radiation and drug therapy. Additionally, we illustrate whether miRNAs can be considered novel therapeutic targets or tools on the basis of the consequences of their expression modulation in PCa experimental models. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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19 pages, 2052 KiB  
Review
Gut Microbiota as Potential Biomarker and/or Therapeutic Target to Improve the Management of Cancer: Focus on Colibactin-Producing Escherichia coli in Colorectal Cancer
by Julie Veziant, Romain Villéger, Nicolas Barnich and Mathilde Bonnet
Cancers 2021, 13(9), 2215; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092215 - 05 May 2021
Cited by 30 | Viewed by 5136
Abstract
The gut microbiota is crucial for physiological development and immunological homeostasis. Alterations of this microbial community called dysbiosis, have been associated with cancers such colorectal cancers (CRC). The pro-carcinogenic potential of this dysbiotic microbiota has been demonstrated in the colon. Recently the role [...] Read more.
The gut microbiota is crucial for physiological development and immunological homeostasis. Alterations of this microbial community called dysbiosis, have been associated with cancers such colorectal cancers (CRC). The pro-carcinogenic potential of this dysbiotic microbiota has been demonstrated in the colon. Recently the role of the microbiota in the efficacy of anti-tumor therapeutic strategies has been described in digestive cancers and in other cancers (e.g., melanoma and sarcoma). Different bacterial species seem to be implicated in these mechanisms: F. nucleatum, B. fragilis, and colibactin-associated E. coli (CoPEC). CoPEC bacteria are prevalent in the colonic mucosa of patients with CRC and they promote colorectal carcinogenesis in susceptible mouse models of CRC. In this review, we report preclinical and clinical data that suggest that CoPEC could be a new factor predictive of poor outcomes that could be used to improve cancer management. Moreover, we describe the possibility of using these bacteria as new therapeutic targets. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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29 pages, 866 KiB  
Review
An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma
by Seán B. Lyne and Bakhtiar Yamini
Cancers 2021, 13(8), 1953; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081953 - 18 Apr 2021
Cited by 29 | Viewed by 5788
Abstract
The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively [...] Read more.
The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In ad-dition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of the literature and clinical trials provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is pos-sible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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17 pages, 3033 KiB  
Review
Alternative Vascularization Mechanisms in Tumor Resistance to Therapy
by Dorina Belotti, Denise Pinessi and Giulia Taraboletti
Cancers 2021, 13(8), 1912; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081912 - 15 Apr 2021
Cited by 30 | Viewed by 3491
Abstract
Blood vessels in tumors are formed through a variety of different mechanisms, each generating vessels with peculiar structural, molecular, and functional properties. This heterogeneity has a major impact on tumor response or resistance to antineoplastic therapies and is now emerging as a promising [...] Read more.
Blood vessels in tumors are formed through a variety of different mechanisms, each generating vessels with peculiar structural, molecular, and functional properties. This heterogeneity has a major impact on tumor response or resistance to antineoplastic therapies and is now emerging as a promising target for strategies to prevent drug resistance and improve the distribution and efficacy of antineoplastic treatments. This review presents evidence of how different mechanisms of tumor vessel formation (vasculogenesis, glomeruloid proliferation, intussusceptive angiogenesis, vasculogenic mimicry, and vessel co-option) affect tumor responses to antiangiogenic and antineoplastic therapies, but also how therapies can promote alternative mechanisms of vessel formation, contributing to tumor recurrence, malignant progression, and acquired drug resistance. We discuss the possibility of tailoring treatment strategies to overcome vasculature-mediated drug resistance or to improve drug distribution and efficacy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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24 pages, 1453 KiB  
Review
Non-Coding RNAs as Biomarkers of Tumor Progression and Metastatic Spread in Epithelial Ovarian Cancer
by Karolina Seborova, Radka Vaclavikova, Lukas Rob, Pavel Soucek and Pavel Vodicka
Cancers 2021, 13(8), 1839; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081839 - 12 Apr 2021
Cited by 12 | Viewed by 2663
Abstract
Ovarian cancer is one of the most common causes of death among gynecological malignancies. Molecular changes occurring in the primary tumor lead to metastatic spread into the peritoneum and the formation of distant metastases. Identification of these changes helps to reveal the nature [...] Read more.
Ovarian cancer is one of the most common causes of death among gynecological malignancies. Molecular changes occurring in the primary tumor lead to metastatic spread into the peritoneum and the formation of distant metastases. Identification of these changes helps to reveal the nature of metastases development and decipher early biomarkers of prognosis and disease progression. Comparing differences in gene expression profiles between primary tumors and metastases, together with disclosing their epigenetic regulation, provides interesting associations with progression and metastasizing. Regulatory elements from the non-coding RNA families such as microRNAs and long non-coding RNAs seem to participate in these processes and represent potential molecular biomarkers of patient prognosis. Progress in therapy individualization and its proper targeting also rely upon a better understanding of interactions among the above-listed factors. This review aims to summarize currently available findings of microRNAs and long non-coding RNAs linked with tumor progression and metastatic process in ovarian cancer. These biomolecules provide promising tools for monitoring the patient’s response to treatment, and further they serve as potential therapeutic targets of this deadly disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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29 pages, 1187 KiB  
Review
Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance
by Debashri Manna and Devanand Sarkar
Cancers 2021, 13(8), 1792; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081792 - 09 Apr 2021
Cited by 15 | Viewed by 2865
Abstract
Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, [...] Read more.
Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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20 pages, 2000 KiB  
Review
Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer
by Marzieh Ehsani, Faith Oluwakemi David and Aria Baniahmad
Cancers 2021, 13(7), 1534; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071534 - 26 Mar 2021
Cited by 40 | Viewed by 4723
Abstract
Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, [...] Read more.
Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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20 pages, 1273 KiB  
Review
The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications
by Martha Wium, Aderonke F. Ajayi-Smith, Juliano D. Paccez and Luiz F. Zerbini
Cancers 2021, 13(7), 1521; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071521 - 25 Mar 2021
Cited by 26 | Viewed by 4851
Abstract
Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of [...] Read more.
Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of chemoresistance. The receptor tyrosine kinase Axl, a member of the TAM family (which includes TYRO3 and MER), plays an important role in the regulation of cellular processes such as proliferation, motility, survival, and immunologic response. The overexpression of Axl is reported in several solid and hematological malignancies, including non-small cell lung, prostate, breast, liver and gastric cancers, and acute myeloid leukaemia. The overexpression of Axl is associated with poor prognosis and the development of resistance to therapy. Reports show that Axl overexpression confers drug resistance in lung cancer and advances the emergence of tolerant cells. Axl is, therefore, an important candidate as a prognostic biomarker and target for anticancer therapies. In this review, we discuss the consequence of Axl upregulation in cancers, provide evidence for its role in cancer progression and the development of drug resistance. We will also discuss the therapeutic potential of Axl in the treatment of cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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24 pages, 1366 KiB  
Review
Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer
by Andreas Domen, Delphine Quatannens, Sara Zanivan, Christophe Deben, Jonas Van Audenaerde, Evelien Smits, An Wouters, Filip Lardon, Geert Roeyen, Yannick Verhoeven, Annelies Janssens, Timon Vandamme, Peter van Dam, Marc Peeters and Hans Prenen
Cancers 2021, 13(5), 987; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13050987 - 27 Feb 2021
Cited by 38 | Viewed by 5301
Abstract
Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types [...] Read more.
Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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16 pages, 2654 KiB  
Review
Extracellular Vesicles: Emerging Modulators of Cancer Drug Resistance
by Fabrizio Fontana, Emanuela Carollo, Genevieve E. Melling and David R. F. Carter
Cancers 2021, 13(4), 749; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040749 - 11 Feb 2021
Cited by 39 | Viewed by 2888
Abstract
Extracellular vesicles (EVs) have recently emerged as crucial modulators of cancer drug resistance. Indeed, it has been shown that they can directly sequester anti-tumor drugs, decreasing their effective concentration at target sites. Moreover, they facilitate the horizontal transfer of specific bioactive cargoes able [...] Read more.
Extracellular vesicles (EVs) have recently emerged as crucial modulators of cancer drug resistance. Indeed, it has been shown that they can directly sequester anti-tumor drugs, decreasing their effective concentration at target sites. Moreover, they facilitate the horizontal transfer of specific bioactive cargoes able to regulate proliferative, apoptotic, and stemness programs in recipient cells, potentially conferring a resistant phenotype to drug-sensitive cancer cells. Finally, EVs can mediate the communication between the tumor and both stromal and immune cells within the microenvironment, promoting treatment escape. In this context, clarifying the EV-driven resistance mechanisms might improve not only tumor diagnosis and prognosis but also therapeutic outcomes. Detailed cellular and molecular events occurring during the development of EV-mediated cancer drug resistance are described in this review article. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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22 pages, 721 KiB  
Review
Cancer Stem Cells—Key Players in Tumor Relapse
by Monica Marzagalli, Fabrizio Fontana, Michela Raimondi and Patrizia Limonta
Cancers 2021, 13(3), 376; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030376 - 20 Jan 2021
Cited by 76 | Viewed by 5127
Abstract
Tumor relapse and treatment failure are unfortunately common events for cancer patients, thus often rendering cancer an uncurable disease. Cancer stem cells (CSCs) are a subset of cancer cells endowed with tumor-initiating and self-renewal capacity, as well as with high adaptive abilities. Altogether, [...] Read more.
Tumor relapse and treatment failure are unfortunately common events for cancer patients, thus often rendering cancer an uncurable disease. Cancer stem cells (CSCs) are a subset of cancer cells endowed with tumor-initiating and self-renewal capacity, as well as with high adaptive abilities. Altogether, these features contribute to CSC survival after one or multiple therapeutic approaches, thus leading to treatment failure and tumor progression/relapse. Thus, elucidating the molecular mechanisms associated with stemness-driven resistance is crucial for the development of more effective drugs and durable responses. This review will highlight the mechanisms exploited by CSCs to overcome different therapeutic strategies, from chemo- and radiotherapies to targeted therapies and immunotherapies, shedding light on their plasticity as an insidious trait responsible for their adaptation/escape. Finally, novel CSC-specific approaches will be described, providing evidence of their preclinical and clinical applications. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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19 pages, 1609 KiB  
Review
Interrupting Neuron—Tumor Interactions to Overcome Treatment Resistance
by Patrick J. Hunt, Katherine E. Kabotyanski, George A. Calin, Tongxin Xie, Jeffrey N. Myers and Moran Amit
Cancers 2020, 12(12), 3741; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123741 - 12 Dec 2020
Cited by 9 | Viewed by 3873
Abstract
Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into [...] Read more.
Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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20 pages, 1163 KiB  
Review
Tumour Dissemination in Multiple Myeloma Disease Progression and Relapse: A Potential Therapeutic Target in High-Risk Myeloma
by Mara N. Zeissig, Andrew C. W. Zannettino and Kate Vandyke
Cancers 2020, 12(12), 3643; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123643 - 04 Dec 2020
Cited by 7 | Viewed by 3416
Abstract
Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a [...] Read more.
Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a feature of advanced disease. In this review, the current understanding of the process of MM PC dissemination and the extrinsic and intrinsic factors potentially driving it are addressed through analysis of patient-derived MM PCs and MM cell lines as well as mouse models of homing and dissemination. In addition, we discuss how patient cytogenetic subgroups that present with highly disseminated disease, such as t(4;14), t(14;16) and t(14;20), suggest that intrinsic properties of MM PC influence their ability to disseminate. Finally, we discuss the possibility of using therapeutic targeting of tumour dissemination to slow disease progression and prevent overt relapse. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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57 pages, 997 KiB  
Review
Mechanisms of Taxane Resistance
by Sara M. Maloney, Camden A. Hoover, Lorena V. Morejon-Lasso and Jenifer R. Prosperi
Cancers 2020, 12(11), 3323; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113323 - 10 Nov 2020
Cited by 86 | Viewed by 10876
Abstract
The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response [...] Read more.
The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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34 pages, 3650 KiB  
Review
Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer
by Elizabeth Varghese, Samson Mathews Samuel, Alena Líšková, Marek Samec, Peter Kubatka and Dietrich Büsselberg
Cancers 2020, 12(8), 2252; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082252 - 12 Aug 2020
Cited by 112 | Viewed by 13235
Abstract
Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the [...] Read more.
Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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21 pages, 1652 KiB  
Review
Hypopigmented Mycosis Fungoides: Loss of Pigmentation Reflects Antitumor Immune Response in Young Patients
by Amelia Martínez Villarreal, Jennifer Gantchev, François Lagacé, Augustin Barolet, Denis Sasseville, Niels Ødum, Yann Vincent Charli-Joseph, Amparo Hernández Salazar and Ivan V. Litvinov
Cancers 2020, 12(8), 2007; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082007 - 22 Jul 2020
Cited by 12 | Viewed by 10576
Abstract
Hypopigmented mycosis fungoides (HMF) is a form of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin’s lymphomas. HMF has a unique set of defining features that include light colored to achromic lesions, a predilection for darker skin phototypes, an early onset [...] Read more.
Hypopigmented mycosis fungoides (HMF) is a form of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin’s lymphomas. HMF has a unique set of defining features that include light colored to achromic lesions, a predilection for darker skin phototypes, an early onset of disease, and predominance of CD8+ T-cells, among others. In the current review, we detail the known pathways of molecular pathogenesis for this lymphoma and posit that an active Th1/cytotoxic antitumor immune response in part explains why this variant is primarily seen in children/adolescents and young adults, who do not exhibit signs of immunosenescence. As a result of this potent cytotoxic response, HMF patients experience mostly favorable overall prognosis, while hypopigmentation may in fact represent a useful surrogate marker of cytotoxic immunity targeting the malignant cells. Understanding the molecular processes behind the specific features that define HMF may lead to improved diagnostic accuracy, personalized prognosis by risk stratification, and improved management of HMF. Moreover, improving our knowledge of HMF may aid our further understanding of other cutaneous lymphomas. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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21 pages, 2525 KiB  
Review
Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment
by Tsubasa Miyazaki, Eiichi Ishikawa, Narushi Sugii and Masahide Matsuda
Cancers 2020, 12(7), 1960; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071960 - 19 Jul 2020
Cited by 19 | Viewed by 4713
Abstract
Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor [...] Read more.
Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Drug Resistance: Emerging Biomarkers and Promising Targets to Overcome Tumor Progression)
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