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Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 7381

Special Issue Editor

Dr. Kathleen Pishas

E-Mail Website
Guest Editor
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
Interests: drug resistance; Ewing sarcoma; ovarian cancer; ABCB1; LSD1; TP53
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a highly complex, adaptive condition that can rapidly develop new phenotypic and genotypic profiles to circumvent therapy. Drug resistance threatens the longevity of drugs and restricts the treatment options for patients, and it is highly common in oncology and infectious diseases. The emergence of drug resistance remains the largest impediment in the quest for a curative cancer treatment, with an estimated 90% of all cancer-related deaths being attributed to chemoresistance. The rapidity with which cancer cells can develop resistance to both classical chemotherapy and targeted agents is startling. With the knowledge that each cubic centimeter of a tumour contains up to one billion cancer cells, novel insights into both primary and acquired resistance mechanisms, including drug detoxification, alterations in drug targets, genomic/epigenetic instability, increased ability to repair DNA damage, reduced susceptibility to apoptosis, as well as the influence of the tumour microenvironment and clonal cooperation, are required to substantially alter therapeutic treatment practices and increase the overall survival rates. Some of these resistance pathways lead to multidrug resistance, generating an increasingly challenging clinical problem.

This Special Issue of IJMS will highlight the recent advances in drug resistance, particularly novel mechanisms and targeted strategies to tackle this global medicine concern. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Kathleen Pishas
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • apoptosis
  • cancer
  • clinical trials
  • chemotherapy
  • drug metabolism
  • drug resistance
  • drug delivery
  • heterogeneity
  • immunotherapy
  • microenvironment

Related Special Issue

Published Papers (6 papers)

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Research

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15 pages, 2827 KiB  
Article
SAHA/5-AZA Enhances Acetylation and Degradation of mutp53, Upregulates p21 and Downregulates c-Myc and BRCA-1 in Pancreatic Cancer Cells
by Michele Di Crosta, Francesca Chiara Ragone, Rossella Benedetti, Gabriella D’Orazi, Maria Saveria Gilardini Montani and Mara Cirone
Int. J. Mol. Sci. 2024, 25(13), 7020; https://doi.org/10.3390/ijms25137020 - 27 Jun 2024
Viewed by 1070
Abstract
Epigenetic changes are common in cancer and include aberrant DNA methylation and histone modifications, including both acetylation or methylation. DNA methylation in the promoter regions and histone deacetylation are usually accompanied by gene silencing, and may lead to the suppression of tumor suppressors [...] Read more.
Epigenetic changes are common in cancer and include aberrant DNA methylation and histone modifications, including both acetylation or methylation. DNA methylation in the promoter regions and histone deacetylation are usually accompanied by gene silencing, and may lead to the suppression of tumor suppressors in cancer cells. An interaction between epigenetic pathways has been reported that could be exploited to more efficiently target aggressive cancer cells, particularly those against which current treatments usually fail, such as pancreatic cancer. In this study, we explored the possibility to combine the DNA demethylating agent 5-AZA with HDAC inhibitor SAHA to treat pancreatic cancer cell lines, focusing on the acetylation of mutp53 and the consequences on its stability, as well as on the interaction of this protein with c-myc and BRCA-1, key molecules in cancer survival. The results obtained suggest that SAHA/5-AZA combination was more effective than single treatments to promote the degradation of mutp53, to upregulate p21 and downregulate c-Myc and BRCA-1, thus increasing DNA damage and cytotoxicity in pancreatic cancer cells. Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)
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17 pages, 4158 KiB  
Article
Identification of New Chemoresistance-Associated Genes in Triple-Negative Breast Cancer by Single-Cell Transcriptomic Analysis
by Spyros Foutadakis, Dimitrios Kordias, Giannis Vatsellas and Angeliki Magklara
Int. J. Mol. Sci. 2024, 25(13), 6853; https://doi.org/10.3390/ijms25136853 - 22 Jun 2024
Viewed by 627
Abstract
Triple-negative breast cancer (TNBC) is a particularly aggressive mammary neoplasia with a high fatality rate, mainly because of the development of resistance to administered chemotherapy, the standard treatment for this disease. In this study, we employ both bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) [...] Read more.
Triple-negative breast cancer (TNBC) is a particularly aggressive mammary neoplasia with a high fatality rate, mainly because of the development of resistance to administered chemotherapy, the standard treatment for this disease. In this study, we employ both bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) to investigate the transcriptional landscape of TNBC cells cultured in two-dimensional monolayers or three-dimensional spheroids, before and after developing resistance to the chemotherapeutic agents paclitaxel and doxorubicin. Our findings reveal significant transcriptional heterogeneity within the TNBC cell populations, with the scRNA-seq identifying rare subsets of cells that express resistance-associated genes not detected by the bulk RNA-seq. Furthermore, we observe a partial shift towards a highly mesenchymal phenotype in chemoresistant cells, suggesting the epithelial-to-mesenchymal transition (EMT) as a prevalent mechanism of resistance in subgroups of these cells. These insights highlight potential therapeutic targets, such as the PDGF signaling pathway mediating EMT, which could be exploited in this setting. Our study underscores the importance of single-cell approaches in understanding tumor heterogeneity and developing more effective, personalized treatment strategies to overcome chemoresistance in TNBC. Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)
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21 pages, 9751 KiB  
Article
A Stem-like Patient-Derived Ovarian Cancer Model of Platinum Resistance Reveals Dissociation of Stemness and Resistance
by Tise Suzuki, Ashlyn Conant, Yeonkyu Jung, Ryan Bax, Ashley Antonissen, Wanqiu Chen, Gary Yu, Yevgeniya J. Ioffe, Charles Wang and Juli J. Unternaehrer
Int. J. Mol. Sci. 2024, 25(7), 3843; https://doi.org/10.3390/ijms25073843 - 29 Mar 2024
Viewed by 956
Abstract
To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its [...] Read more.
To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic–features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer. Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)
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Review

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19 pages, 1459 KiB  
Review
Deciphering Drug Resistance: Investigating the Emerging Role of Hyaluronan Metabolism and Signaling and Tumor Extracellular Matrix in Cancer Chemotherapy
by Daiana L. Vitale, Arianna Parnigoni, Manuela Viola, Evgenia Karousou, Ina Sevic, Paola Moretto, Alberto Passi, Laura Alaniz and Davide Vigetti
Int. J. Mol. Sci. 2024, 25(14), 7607; https://doi.org/10.3390/ijms25147607 - 11 Jul 2024
Viewed by 352
Abstract
Hyaluronan (HA) has gained significant attention in cancer research for its role in modulating chemoresistance. This review aims to elucidate the mechanisms by which HA contributes to chemoresistance, focusing on its interactions within the tumor microenvironment. HA is abundantly present in the extracellular [...] Read more.
Hyaluronan (HA) has gained significant attention in cancer research for its role in modulating chemoresistance. This review aims to elucidate the mechanisms by which HA contributes to chemoresistance, focusing on its interactions within the tumor microenvironment. HA is abundantly present in the extracellular matrix (ECM) and binds to cell-surface receptors such as CD44 and RHAMM. These interactions activate various signaling pathways, including PI3K/Akt, MAPK, and NF-κB, which are implicated in cell survival, proliferation, and drug resistance. HA also influences the physical properties of the tumor stroma, enhancing its density and reducing drug penetration. Additionally, HA-mediated signaling contributes to the epithelial–mesenchymal transition (EMT), a process associated with increased metastatic potential and resistance to apoptosis. Emerging therapeutic strategies aim to counteract HA-induced chemoresistance by targeting HA synthesis, degradation, metabolism, or its binding to CD44. This review underscores the complexity of HA’s role in chemoresistance and highlights the potential for HA-targeted therapies to improve the efficacy of conventional chemotherapeutics. Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)
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Graphical abstract

22 pages, 694 KiB  
Review
Treatment of Double-Refractory Chronic Lymphocytic Leukemia—An Unmet Clinical Need
by Przemysław Zygmunciak, Tadeusz Robak and Bartosz Puła
Int. J. Mol. Sci. 2024, 25(3), 1589; https://doi.org/10.3390/ijms25031589 - 27 Jan 2024
Cited by 3 | Viewed by 2107
Abstract
Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton’s kinase (BTK) have become the main strategies to restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due [...] Read more.
Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton’s kinase (BTK) have become the main strategies to restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due to resistance, adverse effects, and Richter’s transformation. A growing population of patients who have previously used both BTK inhibitors and BCL2 suffer from the constriction of the following regimens. This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double-refractory CLL. Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)
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14 pages, 708 KiB  
Review
Emerging Roles of YES1 in Cancer: The Putative Target in Drug Resistance
by Eunjin Kook, Kyung-Soo Chun and Do-Hee Kim
Int. J. Mol. Sci. 2024, 25(3), 1450; https://doi.org/10.3390/ijms25031450 - 25 Jan 2024
Viewed by 1668
Abstract
Src family kinases (SFKs) are non-receptor tyrosine kinases that are recognized as proto-oncogenic products. Among SFKs, YES1 is frequently amplified and overexpressed in a variety of human tumors, including lung, breast, ovarian, and skin cancers. YES1 plays a pivotal role in promoting cell [...] Read more.
Src family kinases (SFKs) are non-receptor tyrosine kinases that are recognized as proto-oncogenic products. Among SFKs, YES1 is frequently amplified and overexpressed in a variety of human tumors, including lung, breast, ovarian, and skin cancers. YES1 plays a pivotal role in promoting cell proliferation, survival, and invasiveness during tumor development. Recent findings indicate that YES1 expression and activation are associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors in human malignancies. YES1 undergoes post-translational modifications, such as lipidation and nitrosylation, which can modulate its catalytic activity, subcellular localization, and binding affinity for substrate proteins. Therefore, we investigated the diverse mechanisms governing YES1 activation and its impact on critical intracellular signal transduction pathways. We emphasized the function of YES1 as a potential mechanism contributing to the anticancer drug resistance emergence. Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)
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