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Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 39105

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Special Issue Editors

Dr. Mirela Sedic

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Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia
Interests: chemotherapy; chemoresistance; cancer biology; colon cancer; cell signaling; proteomics; lipidomics; sphingolipids; biomarkers; personalised medicine
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Dr. Miran Čoklo

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Centre for Applied Bioanthropology, Institute for Anthropological Research, Zagreb, Croatia
Interests: personalised medicine; colon cancer; biomarkers; head and neck cancer; lipidomics; pharmacogenomics

Special Issue Information

Dear Colleagues,

The development of chemoresistance represents a major hurdle for the successful treatment of cancer. A multitude of scientific findings from recent preclinical and clinical studies have undoubtedly broadened our current knowledge of the mechanisms underlying the development of cancer drug resistance and have paved the way for the design of novel therapeutic strategies for patients with refractory cancer. In particular, numerous genomics studies have already been conducted in different cancer types to uncover major molecular players governing cancer progression and treatment response, with these data being publicly available in different cancer databases and repositories. However, the more comprehensive characterisation of cancer drug resistance encompassing different layers of molecular information (e.g., transcriptomics, proteomics, metabolomics, lipidomics, microRNAs, long non-coding RNAs, medical/mass-spectrometry imaging, etc.) and the integration and analysis of data from public cancer data repositories and newly obtained experimental data using artificial intelligence tools would facilitate the data-driven identification of the key molecular features of chemoresistance. In addition, the discovery of novel biomarkers that would enable treatment response to be monitored for a timely identification of cancer patients with an increased risk for disease recurrence holds promise to improve the management of cancer patients. In this Special Issue of the IJMS, we welcome basic and translational studies that address all issues pertinent to cancer drug resistance, including the following: the discovery of novel molecular mechanisms and druggable targets for chemoresistance; the identification of novel prognostic and predictive biomarkers of chemoresistance to enable patient stratification and to tailor treatment; the application of bioinformatics and artificial intelligence tools for drug response prediction, risk stratification and the elucidation of the chemoresistance mechanisms by integrating different molecular information; and the discovery of novel combinations of clinically approved anticancer drugs with chemotherapy-sensitising agents to overcome chemoresistance in cancer patients.

Dr. Mirela Sedic
Dr. Miran Čoklo
Guest Editors

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Keywords

chemoresistance
biomarker
artificial intelligence
bioinformatics
-omics
anti-cancer drug response prediction
risk stratification
rational cancer treatment combinations

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Published Papers (12 papers)

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Research

Jump to: Review

14 pages, 7266 KiB

Open AccessArticle

Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma

by Marika A. Franczak, Oliwia Krol, Gabriela Harasim, Agata Jedrzejewska, Nadia Zaffaroni, Carlotta Granchi, Filippo Minutolo, Amir Avan, Elisa Giovannetti, Ryszard T. Smolenski and Godefridus J. Peters

Int. J. Mol. Sci. 2023, 24(9), 7771; https://doi.org/10.3390/ijms24097771 - 24 Apr 2023

Cited by 7 | Viewed by 2350

Abstract

Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. The prognostic role of key effectors of glycolytic metabolism in MM prompted our studies on the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD⁺ metabolism, glycolysis and mitochondrial respiration. The antiproliferative activity of GLUT-1 (PGL13, PGL14) and LDH-A (NHI-1, NHI-2) inhibitors, alone and in combination, were tested with the sulforhodamine-B assay in peritoneal (MESO-II, STO) and pleural (NCI-H2052 and NCI-H28) MM and non-cancerous (HMEC-1) cells. Effects on energy metabolism were measured by both analysis of nucleotides using RP-HPLC and evaluation of glycolysis and respiration parameters using a Seahorse Analyzer system. All compounds reduced the growth of MM cells in the µmolar range. Interestingly, in H2052 cells, PGL14 decreased ATP concentration from 37 to 23 and NAD⁺ from 6.5 to 2.3 nmol/mg protein. NHI-2 reduced the ATP/ADP ratio by 76%. The metabolic effects of the inhibitors were stronger in pleural MM and in combination, while in HMEC-1 ATP reduction was 10% lower compared to that of the H2052 cells, and we observed a minor influence on mitochondrial respiration. To conclude, both inhibitors showed cytotoxicity in MM cells, associated with a decrease in ATP and NAD⁺, and were synergistic in the cells with the highest metabolic modulation. This underlines cellular energy metabolism as a potential target for combined treatments in selected cases of MM. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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20 pages, 5718 KiB

Open AccessArticle

GSK2801 Reverses Paclitaxel Resistance in Anaplastic Thyroid Cancer Cell Lines through MYCN Downregulation

by Elisabetta Molteni, Federica Baldan, Giuseppe Damante and Lorenzo Allegri

Int. J. Mol. Sci. 2023, 24(6), 5993; https://doi.org/10.3390/ijms24065993 - 22 Mar 2023

Cited by 4 | Viewed by 2375

Abstract

Anaplastic thyroid cancer (ATC) is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. Treatment with taxanes (such as paclitaxel) is an important approach in counteracting ATC or slowing its progression in tumors without known genetic aberrations or those which are unresponsive to other treatments. Unfortunately, resistance often develops and, for this reason, new therapies that overcome taxane resistance are needed. In this study, effects of inhibition of several bromodomain proteins in paclitaxel-resistant ATC cell lines were investigated. GSK2801, a specific inhibitor of BAZ2A, BAZ2B and BRD9, was effective in resensitizing cells to paclitaxel. In fact, when used in combination with paclitaxel, it was able to reduce cell viability, block the ability to form colonies in an anchor-independent manner, and strongly decrease cell motility. After RNA-seq following treatment with GSK2801, we focused our attention on MYCN. Based on the hypothesis that MYCN was a major downstream player in the biological effects of GSK2801, we tested a specific inhibitor, VPC-70619, which showed effective biological effects when used in association with paclitaxel. This suggests that the functional deficiency of MYCN determines a partial resensitization of the cells examined and, ultimately, that a substantial part of the effect of GSK2801 results from inhibition of MYCN expression. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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21 pages, 3518 KiB

Open AccessArticle

Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

by Angela Patricia Moreno-Londoño, María Cristina Castañeda-Patlán, Miguel Angel Sarabia-Sánchez, Marina Macías-Silva and Martha Robles-Flores

Int. J. Mol. Sci. 2023, 24(6), 5252; https://doi.org/10.3390/ijms24065252 - 9 Mar 2023

Cited by 10 | Viewed by 2734

Abstract

The presence of cancer stem cells (CSCs) has been associated with the induction of drug resistance and disease recurrence after therapy. 5-Fluorouracil (5FU) is widely used as the first-line treatment of colorectal cancer (CRC). However, its effectiveness may be limited by the induction of drug resistance in tumor cells. The Wnt pathway plays a key role in the development and CRC progression, but it is not clearly established how it is involved in CSCs resistance to treatment. This work aimed to investigate the role played by the canonical Wnt/β-catenin pathway in CSCs resistance to 5FU treatment. Using tumor spheroids as a model of CSCs enrichment of CRC cell lines with different Wnt/β-catenin contexts, we found that 5FU induces in all CRC spheroids tested cell death, DNA damage, and quiescence, but in different proportions for each one: RKO spheroids were very sensitive to 5FU, while SW480 were less susceptible, and the SW620 spheroids, the metastatic derivative of SW480 cells, displayed the highest resistance to death, high clonogenic capacity, and the highest ability for regrowth after 5FU treatment. Activating the canonical Wnt pathway with Wnt3a in RKO spheroids decreased the 5FU-induced cell death. But the Wnt/β-catenin pathway inhibition with Adavivint alone or in combination with 5FU in spheroids with aberrant activation of this pathway produced a severe cytostatic effect compromising their clonogenic capacity and diminishing the stem cell markers expression. Remarkably, this combined treatment also induced the survival of a small cell subpopulation that could exit the arrest, recover SOX2 levels, and re-grow after treatment. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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18 pages, 10673 KiB

Open AccessArticle

Dual Inhibition of EGFR and IGF-1R Signaling Leads to Enhanced Antitumor Efficacy against Esophageal Squamous Cancer

by Jia Kang, Zanzan Guo, Haoqi Zhang, Rongqi Guo, Xiaofei Zhu and Xiaofang Guo

Int. J. Mol. Sci. 2022, 23(18), 10382; https://doi.org/10.3390/ijms231810382 - 8 Sep 2022

Cited by 13 | Viewed by 2725

Abstract

Both the epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) have been implicated in the development of cancers, and the increased expression of both receptors has been observed in esophageal cancer. However, the tyrosine kinase inhibitors of both receptors have thus far failed to provide clinical benefits for esophageal cancer patients. Studies have confirmed the complicated crosstalks that exist between the EGFR and IGF-1R pathways. The EGFR and IGF-1R signals act as mutual compensation pathways, thereby conveying resistance to EGFR or IGF-1R inhibitors when used alone. This study evaluated the antitumor efficacy of the EGFR/HER2 inhibitors, gefitinib and lapatinib, in combination with the IGF-1R inhibitor, linsitinib, on the esophageal squamous cell carcinoma (ESCC). Gefitinib or lapatinib, in combination with linsitinib, synergistically inhibited the proliferation, migration, and invasion of ESCC cells, caused significant cell cycle arrest, and induced marked cell apoptosis. Their combination demonstrated stronger inhibition on the activation of EGFR, HER2, and IGF-1R as well as the downstream signaling molecules. In vivo, the addition of linsitinib to gefitinib or lapatinib also potentiated the inhibition effects on the growth of xenografts. Our results suggest the next clinical exploration of the combination of gefitinib or lapatinib with linsitinib in the treatment of ESCC patients. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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17 pages, 3218 KiB

Open AccessArticle

Antigen Peptide Transporter 1 (TAP1) Promotes Resistance to MEK Inhibitors in Pancreatic Cancers

by Boya Li, Yu Feng, Qiaoyun Hou, Yan Fu and Yongzhang Luo

Int. J. Mol. Sci. 2022, 23(13), 7168; https://doi.org/10.3390/ijms23137168 - 28 Jun 2022

Cited by 5 | Viewed by 2360

Abstract

Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors show limited benefit in Kirsten rat sarcoma (KRAS) mutant pancreatic cancer due to drug resistance. To identify mechanisms of resistance to MEK inhibitor (MEKi), we employed a differential expression analysis of MEKi-sensitive versus MEKi-resistant KRAS-mutant pancreatic cancer cell lines. Here, we report that the antigen peptide transporter 1 (TAP1) expression levels of MEKi-resistant cell lines were notably higher than those of MEKi-sensitive cell lines. Suppression of TAP1 significantly sensitized the MEKi-resistant pancreatic ductal adenocarcinoma (PDAC) cells to MEKi and induced higher apoptotic rate in vitro. Moreover, knockdown of TAP1 in MEKi-resistant tumor significantly decreased tumor growth in vivo. Consistently, overexpression of TAP1 in sensitive PDAC cells resulted in increased resistance to MEKi, both in vitro and in vivo. Mechanistic studies demonstrated that TAP1 promoted chemoresistance by enhancing the transport of MEKi out of PDAC cells, leading to reduced intracellular MEKi concentration and attenuated inhibition of KRAS signaling pathways. Moreover, TAP1 expression increased spheroid formation abilities of PDAC cells. These findings suggest that TAP1 could serve as a potential marker for predicting the response of patients to MEKi. Combination of TAP1 suppression and MEKi may provide a novel therapeutic strategy for PDAC treatment. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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Review

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22 pages, 767 KiB

Open AccessReview

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

by Tina Petrić and Maja Sabol

Int. J. Mol. Sci. 2023, 24(6), 5293; https://doi.org/10.3390/ijms24065293 - 10 Mar 2023

Cited by 5 | Viewed by 2930

Abstract

Prostate cancer (PC) is the third most frequently diagnosed cancer worldwide and the second most frequent in men. Several risk factors can contribute to the development of PC, and those include age, family history, and specific genetic mutations. So far, drug testing in PC, as well as in cancer research in general, has been performed on 2D cell cultures. This is mainly because of the vast benefits these models provide, including simplicity and cost effectiveness. However, it is now known that these models are exposed to much higher stiffness; lose physiological extracellular matrix on artificial plastic surfaces; and show changes in differentiation, polarization, and cell–cell communication. This leads to the loss of crucial cellular signaling pathways and changes in cell responses to stimuli when compared to in vivo conditions. Here, we emphasize the importance of a diverse collection of 3D PC models and their benefits over 2D models in drug discovery and screening from the studies done so far, outlining their benefits and limitations. We highlight the differences between the diverse types of 3D models, with the focus on tumor–stroma interactions, cell populations, and extracellular matrix composition, and we summarize various standard and novel therapies tested on 3D models of PC for the purpose of raising awareness of the possibilities for a personalized approach in PC therapy. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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24 pages, 1844 KiB

Open AccessReview

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

by Hyein Jo, Kyeonghee Shim and Dooil Jeoung

Int. J. Mol. Sci. 2023, 24(4), 4225; https://doi.org/10.3390/ijms24044225 - 20 Feb 2023

Cited by 8 | Viewed by 3022

Abstract

RNA methylations play critical roles in RNA processes, including RNA splicing, nuclear export, nonsense-mediated RNA decay, and translation. Regulators of RNA methylations have been shown to be differentially expressed between tumor tissues/cancer cells and adjacent tissues/normal cells. N6-methyladenosine (m6A) is the most prevalent internal modification of RNAs in eukaryotes. m6A regulators include m6A writers, m6A demethylases, and m6A binding proteins. Since m6A regulators play important roles in regulating the expression of oncogenes and tumor suppressor genes, targeting m6A regulators can be a strategy for developing anticancer drugs. Anticancer drugs targeting m6A regulators are in clinical trials. m6A regulator-targeting drugs could enhance the anticancer effects of current chemotherapy drugs. This review summarizes the roles of m6A regulators in cancer initiation and progression, autophagy, and anticancer drug resistance. The review also discusses the relationship between autophagy and anticancer drug resistance, the effect of high levels of m6A on autophagy and the potential values of m6A regulators as diagnostic markers and anticancer therapeutic targets. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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24 pages, 2565 KiB

Open AccessReview

The Potential of Senescence as a Target for Developing Anticancer Therapy

by Hyein Jo, Kyeonghee Shim and Dooil Jeoung

Int. J. Mol. Sci. 2023, 24(4), 3436; https://doi.org/10.3390/ijms24043436 - 8 Feb 2023

Cited by 7 | Viewed by 4225

Abstract

Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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23 pages, 410 KiB

Open AccessReview

Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents

by Mariyam Kim, Laura Bakyt, Azamat Akhmetkaliyev, Dana Toktarkhanova and Denis Bulanin

Int. J. Mol. Sci. 2023, 24(3), 2122; https://doi.org/10.3390/ijms24032122 - 20 Jan 2023

Cited by 7 | Viewed by 3689

Abstract

Cancer stem cells are found in many cancer types. They comprise a distinct subpopulation of cells within the tumor that exhibit properties of stem cells. They express a number of cell surface markers, such as CD133, CD44, ALDH, and EpCAM, as well as embryonic transcription factors Oct4, Nanog, and SOX2. CSCs are more resistant to conventional chemotherapy and can potentially drive tumor relapse. Therefore, it is essential to understand the molecular mechanisms that drive chemoresistance and to target them with specific therapy effectively. Highly conserved developmental signaling pathways such as Wnt, Hedgehog, and Notch are commonly reported to play a role in CSCs chemoresistance development. Studies show that particular pathway inhibitors combined with conventional therapy may re-establish sensitivity to the conventional therapy. Another significant contributor of chemoresistance is a specific tumor microenvironment. Surrounding stroma in the form of cancer-associated fibroblasts, macrophages, endothelial cells, and extracellular matrix components produce cytokines and other factors, thus creating a favorable environment and decreasing the cytotoxic effects of chemotherapy. Anti-stromal agents may potentially help to overcome these effects. Epigenetic changes and autophagy were also among the commonly reported mechanisms of chemoresistance. This review provides an overview of signaling pathway components involved in the development of chemoresistance of CSCs and gathers evidence from experimental studies in which CSCs can be re-sensitized to conventional chemotherapy agents across different cancer types. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

14 pages, 614 KiB

Open AccessReview

Cell-Free DNA Fragmentomics: A Promising Biomarker for Diagnosis, Prognosis and Prediction of Response in Breast Cancer

by Caterina Gianni, Michela Palleschi, Filippo Merloni, Giandomenico Di Menna, Marianna Sirico, Samanta Sarti, Alessandra Virga, Paola Ulivi, Lorenzo Cecconetto, Marita Mariotti and Ugo De Giorgi

Int. J. Mol. Sci. 2022, 23(22), 14197; https://doi.org/10.3390/ijms232214197 - 17 Nov 2022

Cited by 14 | Viewed by 4771

Abstract

Identifying novel circulating biomarkers predictive of response and informative about the mechanisms of resistance, is the new challenge for breast cancer (BC) management. The integration of omics information will gradually revolutionize the clinical approach. Liquid biopsy is being incorporated into the diagnostic and decision-making process for the treatment of BC, in particular with the analysis of circulating tumor DNA, although with some relevant limitations, including costs. Circulating cell-free DNA (cfDNA) fragmentomics and its integrity index may become a cheaper, noninvasive biomarker that could provide significant additional information for monitoring response to systemic treatments in BC. The purpose of our review is to focus on the available research on cfDNA integrity and its features as a biomarker of diagnosis, prognosis and response to treatments in BC, highlighting new perspectives and critical issues for future applications. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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15 pages, 2074 KiB

Open AccessReview

Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance

by Haozhe Zhang, Yi Zhou, Zengzhen Xing, Rajiv Kumar Sah, Junqi Hu and Hailiang Hu

Int. J. Mol. Sci. 2022, 23(21), 13521; https://doi.org/10.3390/ijms232113521 - 4 Nov 2022

Cited by 12 | Viewed by 3440

Abstract

All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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24 pages, 2622 KiB

Open AccessReview

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

by Hyein Jo, Kyeonghee Shim and Dooil Jeoung

Int. J. Mol. Sci. 2022, 23(17), 9592; https://doi.org/10.3390/ijms23179592 - 24 Aug 2022

Cited by 8 | Viewed by 3283

Abstract

Histone deacetylases (HDACs) regulate gene expression through the epigenetic modification of chromatin structure. HDAC6, unlike many other HDACs, is present in the cytoplasm. Its deacetylates non-histone proteins and plays diverse roles in cancer cell initiation, proliferation, autophagy, and anti-cancer drug resistance. The development of HDAC6-specific inhibitors has been relatively successful. Mechanisms of HDAC6-promoted anti-cancer drug resistance, cancer cell proliferation, and autophagy are discussed. The relationship between autophagy and anti-cancer drug resistance is discussed. The effects of combination therapy, which includes HDAC6 inhibitors, on the sensitivity of cancer cells to chemotherapeutics and immune checkpoint blockade are presented. A summary of clinical trials involving HDAC6-specific inhibitors is also presented. This review presents HDAC6 as a valuable target for developing anti-cancer drugs. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)

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