International Journal of Molecular Sciences

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16 pages, 1523 KiB

Open AccessArticle

Characterization of Chemoresistance in Pancreatic Cancer: A Look at MDR-1 Polymorphisms and Expression in Cancer Cells and Patients

by Giulia Girolimetti, Barbara Balena, Paola Cordella, Tiziano Verri, Leonardo Henry Eusebi, Maria Pia Bozzetti, Cecilia Bucci and Flora Guerra

Int. J. Mol. Sci. 2024, 25(15), 8515; https://doi.org/10.3390/ijms25158515 - 4 Aug 2024

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Abstract

Pancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is [...] Read more.

Pancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is also characterized by a high chemoresistance, due in part to the activity of the ATP Binding Cassette (ABC) pumps accounting for the reduction in the intracellular concentration of the drugs. In this work, we analyze the occurrence of single-nucleotide polymorphisms (SNPs) in the MDR-1 gene, in different pancreatic cancer cell lines, and in tissues from pancreatic cancer patients by DNA sequencing, as well as the expression levels of MDR-1 mRNA and protein, by qRT-PCR and Western Blot analysis. We found that gemcitabine-resistant cells, in conjunction with homozygosis of analyzed SNPs, showed high MDR-1 basal levels with further increases after gemcitabine treatment. Nevertheless, we did not observe in the human PDAC samples a correlation between the level of MDR-1 mRNA and protein expression and SNPs. Preliminary, we conclude that in our small cohort, these SNPs cannot be used as molecular markers for predicting the levels of MDR-1 mRNA/protein levels and drug responses in patients with PDAC. Full article

(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)

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15 pages, 2827 KiB

Open AccessArticle

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

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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

Open AccessArticle

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

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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

Open AccessArticle

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

Cited by 1 | Viewed by 1406

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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25 pages, 812 KiB

Open AccessReview

Multilevel Mechanisms of Cancer Drug Resistance

by Malgorzata Roszkowska

Int. J. Mol. Sci. 2024, 25(22), 12402; https://doi.org/10.3390/ijms252212402 - 19 Nov 2024

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Abstract

Cancer drug resistance represents one of the most significant challenges in oncology and manifests through multiple interconnected molecular and cellular mechanisms. Objective: To provide a comprehensive analysis of multilevel processes driving treatment resistance by integrating recent advances in understanding genetic, epigenetic, and microenvironmental [...] Read more.

Cancer drug resistance represents one of the most significant challenges in oncology and manifests through multiple interconnected molecular and cellular mechanisms. Objective: To provide a comprehensive analysis of multilevel processes driving treatment resistance by integrating recent advances in understanding genetic, epigenetic, and microenvironmental factors. This is a systematic review of the recent literature focusing on the mechanisms of cancer drug resistance, including genomic studies, clinical trials, and experimental research. Key findings include the following: (1) Up to 63% of somatic mutations can be heterogeneous within individual tumors, contributing to resistance development; (2) cancer stem cells demonstrate enhanced DNA repair capacity and altered metabolic profiles; (3) the tumor microenvironment, including cancer-associated fibroblasts and immune cell populations, plays a crucial role in promoting resistance; and (4) selective pressure from radiotherapy drives the emergence of radioresistant phenotypes through multiple adaptive mechanisms. Understanding the complex interplay between various resistance mechanisms is essential for developing effective treatment strategies. Future therapeutic approaches should focus on combination strategies that target multiple resistance pathways simultaneously, guided by specific biomarkers. Full article

(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)

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31 pages, 1385 KiB

Open AccessReview

Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors

by Luciana Alexandra Pavelescu, Robert Mihai Enache, Oana Alexandra Roşu, Monica Profir, Sanda Maria Creţoiu and Bogdan Severus Gaspar

Int. J. Mol. Sci. 2024, 25(17), 9659; https://doi.org/10.3390/ijms25179659 - 6 Sep 2024

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Abstract

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor [...] Read more.

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies. Full article

(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies, 2nd Edition)

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19 pages, 1459 KiB

Open AccessReview

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

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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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22 pages, 694 KiB

Open AccessReview

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 9 | Viewed by 2887

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

Open AccessReview

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 2290

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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