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Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies

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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: closed (15 May 2023) | Viewed by 22685

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Special Issue Editors

Dr. Kathleen Pishas

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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

Dr. Elizabeth Christie

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Guest Editor

Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Interests: circulating DNA; next-generation sequencing; ovarian cancer

Dr. Dane Cheasley

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Guest Editor

Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Interests: ovarian cancer; breast cancer; Genomics; Genetics; somatic; germline; rare cancers

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 centimetre 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
Dr. Elizabeth Christie
Dr. Dane Cheasley
Guest Editors

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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

Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (9 papers)

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Research

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16 pages, 1300 KiB

Open AccessArticle

ELK1/MTOR/S6K1 Pathway Contributes to Acquired Resistance to Gefitinib in Non-Small Cell Lung Cancer

by Lei Zhao, Yifang Wang, Xin Sun, Xiujuan Zhang, Nicole Simone and Jun He

Int. J. Mol. Sci. 2024, 25(4), 2382; https://doi.org/10.3390/ijms25042382 - 17 Feb 2024

Viewed by 1037

Abstract

The development of acquired resistance to small molecule tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) signaling has hindered their efficacy in treating non-small cell lung cancer (NSCLC) patients. Our previous study showed that constitutive activation of the 70 kDa ribosomal protein S6 kinase 1 (S6K1) contributes to the acquired resistance to EGFR-TKIs in NSCLC cell lines and xenograft tumors in nude mice. However, the regulatory mechanisms underlying S6K1 constitutive activation in TKI-resistant cancer cells have not yet been explored. In this study, we recapitulated this finding by taking advantage of a gefitinib-resistant patient-derived xenograft (PDX) model established through a number of passages in mice treated with increasing doses of gefitinib. The dissociated primary cells from the resistant PDX tumors (PDX-R) displayed higher levels of phosphor-S6K1 expression and were resistant to gefitinib compared to cells from passage-matched parental PDX tumors (PDX-P). Both genetic and pharmacological inhibition of S6K1 increased sensitivity to gefitinib in PDX-R cells. In addition, both total and phosphorylated mechanistic target of rapamycin kinase (MTOR) levels were upregulated in PDX-R and gefitinib-resistant PC9G cells. Knockdown of MTOR by siRNA decreased the expression levels of total and phosphor-S6K1 and increased sensitivity to gefitinib in PDX-R and PC9G cells. Moreover, a transcription factor ELK1, which has multiple predicted binding sites on the MTOR promoter, was also upregulated in PDX-R and PC9G cells, while the knockdown of ELK1 led to decreased expression of MTOR and S6K1. The chromatin immunoprecipitation (ChIP)-PCR assay showed the direct binding between ELK1 and the MTOR promoter, and the luciferase reporter assay further indicated that ELK1 could upregulate MTOR expression through tuning up its transcription. Silencing ELK1 via siRNA transfection improved the efficacy of gefitinib in PDX-R and PC9G cells. These results support the notion that activation of ELK1/MTOR/S6K1 signaling contributes to acquired resistance to gefitinib in NSCLC. The findings in this study shed new light on the mechanism for acquired EGFR-TKI resistance and provide potential novel strategies by targeting the ELK1/MTOR/S6K1 pathway. Full article

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

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15 pages, 3418 KiB

Open AccessArticle

Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor

by Yen-Hsiang Huang, Ling-Yen Chiu, Jeng-Sen Tseng, Kuo-Hsuan Hsu, Chang-Han Chen, Gwo-Tarng Sheu and Tsung-Ying Yang

Int. J. Mol. Sci. 2024, 25(1), 616; https://doi.org/10.3390/ijms25010616 - 3 Jan 2024

Cited by 1 | Viewed by 1097

Abstract

Lung cancer is considered the number one cause of cancer-related deaths worldwide. Although current treatments initially reduce the lung cancer burden, relapse occurs in most cases; the major causes of mortality are drug resistance and cancer stemness. Recent investigations have provided evidence that shikonin generates various bioactivities related to the treatment of cancer. We used shikonin to treat multi-resistant non-small lung cancer cells (DOC-resistant A549/D16, VCR-resistant A549/V16 cells) and defined the anti-cancer efficacy of shikonin. Our results showed shikonin induces apoptosis in these ABCB1-dependent and independent chemoresistance cancer sublines. Furthermore, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation. Concomitantly, the mRNA level and protein of stemness genes (Nanog and Oct4) were repressed significantly on both sublines. Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin. We further applied several signaling pathway inhibitors that have been used in anti-cancer clinical trials to test whether shikonin is suitable as a sensitizer for various signaling pathway inhibitors. In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin’s anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy. Full article

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

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18 pages, 5481 KiB

Open AccessArticle

Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling

by Vladlena Pfeifer, Heiko Weber, Yuanyuan Wang, Martin Schlesinger, Christian Gorzelanny and Gerd Bendas

Int. J. Mol. Sci. 2023, 24(6), 5452; https://doi.org/10.3390/ijms24065452 - 13 Mar 2023

Cited by 1 | Viewed by 1997

Abstract

Heparan sulfate proteoglycans (HSPGs) possess various functions driving malignancy of tumors. However, their impact on tumor cell sensitivity to cytotoxic treatment is far less understood. Aiming to investigate this, we depleted HSPGs by downregulating Exostosin 1 (EXT1), a key enzyme in HS formation, or upregulating heparanase in human MV3 human melanoma cells, and investigated their response to cytotoxic drugs. Cytotoxicity of trametinib, doxorubicin, and mitoxantrone was detected by MTT assay. Insights into intracellular signaling was provided by kinome protein profiler array, and selected kinases were inhibited to investigate their impact on cell sensitization and migratory dynamics. EXT1 knockdown (EXT1kd) in MV3 cells affected the activity of doxorubicin and mitoxantrone, significantly increasing EC₅₀ values two- or fourfold, respectively. Resistance formation was scarcely related to HSPG deficiency, suggested by enzymatic cleavage of HSPG in control cells. Notably, EXT1kd induced an upregulation of EGFR signaling via JNK and MEK/ERK, and hence blocking these kinases returned resistance to a sensitive level. JNK appeared as a key signal component, also inducing higher migratory activity of EXT1kd cells. Furthermore, EXT1kd upregulated thrombotic properties of MV3 cells, indicated by tissue factor and PAR-1 expression, functionally reflected by a stronger activation of platelet aggregation. EXT1 was confirmed to act as a tumor suppressor, shown here for the first time to affect chemosensitivity of melanoma cells. Full article

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

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18 pages, 4224 KiB

Open AccessArticle

Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer

by Helena Muley, Karmele Valencia, Josefina Casas, Bea Moreno, Luis Botella, Fernando Lecanda, Rut Fadó and Núria Casals

Int. J. Mol. Sci. 2023, 24(2), 946; https://doi.org/10.3390/ijms24020946 - 4 Jan 2023

Cited by 1 | Viewed by 1876

Abstract

Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy. Full article

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

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25 pages, 7597 KiB

Open AccessArticle

The Antineoplastic Effect of Carboplatin Is Potentiated by Combination with Pitavastatin or Metformin in a Chemoresistant High-Grade Serous Carcinoma Cell Line

by Mariana Nunes, Diana Duarte, Nuno Vale and Sara Ricardo

Int. J. Mol. Sci. 2023, 24(1), 97; https://doi.org/10.3390/ijms24010097 - 21 Dec 2022

Cited by 4 | Viewed by 1997

Abstract

The combination of Carboplatin with Paclitaxel is the mainstay treatment for high-grade serous carcinoma; however, many patients with advanced disease undergo relapse due to chemoresistance. Drug repurposing coupled with a combination of two or more compounds with independent mechanisms of action has the potential to increase the success rate of the antineoplastic treatment. The purpose of this study was to explore whether the combination of Carboplatin with repurposed drugs led to a therapeutic benefit. Hence, we assessed the cytotoxic effects of Carboplatin alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumoral models, i.e., Carboplatin (OVCAR8) and Carboplatin-Paclitaxel (OVCAR8 PTX R P) chemoresistant cell lines and in a non-tumoral (HOSE6.3) cell line. Cellular viability was measured using the Presto Blue assay, and the synergistic interactions were evaluated using the Chou–Talalay, Bliss Independence and Highest Single Agent reference models. Combining Carboplatin with Pitavastatin or Metformin displayed the highest cytotoxic effect and the strongest synergism among all combinations for OVCAR8 PTX R P cells, resulting in a chemotherapeutic effect superior to Carboplatin as a single agent. Concerning HOSE6.3 cells, combining Carboplatin with almost all the repurposed drugs demonstrated a safe pharmacological profile. Overall, we propose that Pitavastatin or Metformin could act synergistically in combination with Carboplatin for the management of high-grade serous carcinoma patients with a Carboplatin plus Paclitaxel resistance profile. Full article

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

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13 pages, 3006 KiB

Open AccessArticle

Inhibition of TIGAR Increases Exogenous p53 and Cisplatin Combination Sensitivity in Lung Cancer Cells by Regulating Glycolytic Flux

by Jiaying Fu, Sihang Yu, Xiyao Zhao, Chaoke Zhang, Luyan Shen, Yanan Liu and Huimei Yu

Int. J. Mol. Sci. 2022, 23(24), 16034; https://doi.org/10.3390/ijms232416034 - 16 Dec 2022

Cited by 2 | Viewed by 1492

Abstract

The metabolism and apoptosis of tumor cells are important factors that increase their sensitivity to chemotherapeutic drugs. p53 and cisplatin not only induce tumor cell apoptosis, but also regulate the tumor cell metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) can inhibit glycolysis and promote more glucose metabolism in the pentose phosphate pathway. We speculate that the regulation of the TIGAR by the combination therapy of p53 and cisplatin plays an important role in increasing the sensitivity of tumor cells to cisplatin. In this study, we found that the combined treatment of p53 and cisplatin was able to inhibit the mitochondrial function, promote mitochondrial pathway-induced apoptosis, and increase the sensitivity. Furthermore, the expression of the TIGAR was inhibited after a combined p53 and cisplatin treatment, the features of the TIGAR that regulate the pentose phosphate pathway were inhibited, the glucose flux shifted towards glycolysis, and the localization of the complex of the TIGAR and Hexokinase 2 (HK2) on the mitochondria was also reduced. Therefore, the combined treatment of p53 and cisplatin may modulate a glycolytic flux through the TIGAR, altering the cellular metabolic patterns while increasing apoptosis. Taken together, our findings reveal that the TIGAR may serve as a potential therapeutic target to increase the sensitivity of lung cancer A549 cells to cisplatin. Full article

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

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Review

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14 pages, 6138 KiB

Open AccessReview

Evolution-Informed Strategies for Combating Drug Resistance in Cancer

by Kristi Lin-Rahardja, Davis T. Weaver, Jessica A. Scarborough and Jacob G. Scott

Int. J. Mol. Sci. 2023, 24(7), 6738; https://doi.org/10.3390/ijms24076738 - 4 Apr 2023

Cited by 5 | Viewed by 2436

Abstract

The ever-changing nature of cancer poses the most difficult challenge oncologists face today. Cancer’s remarkable adaptability has inspired many to work toward understanding the evolutionary dynamics that underlie this disease in hopes of learning new ways to fight it. Eco-evolutionary dynamics of a tumor are not accounted for in most standard treatment regimens, but exploiting them would help us combat treatment-resistant effectively. Here, we outline several notable efforts to exploit these dynamics and circumvent drug resistance in cancer. Full article

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

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22 pages, 1592 KiB

Open AccessReview

Cancer Resistance to Immunotherapy: Molecular Mechanisms and Tackling Strategies

by Son Hai Vu, Preethi Vetrivel, Jongmin Kim and Myeong-Sok Lee

Int. J. Mol. Sci. 2022, 23(18), 10906; https://doi.org/10.3390/ijms231810906 - 18 Sep 2022

Cited by 8 | Viewed by 3693

Abstract

Cancer immunotherapy has fundamentally altered cancer treatment; however, its efficacy is limited to a subset of patients in most clinical settings. The immune system plays a key role in cancer progression from tumor initiation to the metastatic state. Throughout the treatment course, communications between the immune cells in the tumor microenvironment and the immune macroenvironment, as well as interactions between the immune system and cancer cells, are dynamic and constantly evolving. To improve the clinical benefit for patients who do not respond completely to immunotherapy, the molecular mechanisms of resistance to immunotherapy must be elucidated in order to develop effective strategies to overcome resistance. In an attempt to improve and update the current understanding of the molecular mechanisms that hinder immunotherapy, we discuss the molecular mechanisms of cancer resistance to immunotherapy and the available treatment strategies. Full article

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

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18 pages, 2508 KiB

Open AccessReview

PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

by Dongha Kim and Hye Jin Nam

Int. J. Mol. Sci. 2022, 23(15), 8412; https://doi.org/10.3390/ijms23158412 - 29 Jul 2022

Cited by 28 | Viewed by 5646

Abstract

PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage. Full article

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

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