Special Issue "Cancer Chemoresistance"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 October 2018)

Special Issue Editor

Guest Editor
Dr. Helen M. Coley

Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
Website | E-Mail
Phone: +44 (0) 1483 689701
Interests: Drug resistance; Breast cancer; Ovarian cancer; Platinum resistance; New targeted therapies; Epithelial-mesenchymal-transition

Special Issue Information

Dear Colleagues,

In line with numerous other therapeutic agents, the success of cancer drugs is hindered by the development of clinical drug resistance. The scientific community has mounted a considerable effort in order to understand the underlying mechanisms associated with anticancer drug resistance, over a number of decades. These lines of enquiries have resulted in an enrichment of our knowledge of tumour cell biology—but still leave the oncologist with the day-to-day problem of clinical drug resistance.

Identified molecular pathways that can lead to the development of clinical drug resistance include oncogenic drivers, such as EGFR, PI3K/Akt, disrupted DNA repair, cell death pathways, such as apoptosis and autophagy, the presence of ABC transporters and the process of epithelial-mesenchymal-transition (EMT). Much of this work has been supported by developments in bioinformatics, which make use of open-access databases.

In addition to the issues surrounding the use of cytotoxic drugs associated with standard chemotherapy, new targeted agents such as trastuzumab, lapatinib and gefitinib are also known to be associated with the development of gradual clinical drug resistance. Indeed, some of the mechanisms associated with cytotoxic drugs are shared by some of the targeted cancer therapeutic agents. The overall objective for the cancer scientist is to work hand in hand with the oncologist to find ways to predict in advance clinical drug resistance by the use of biomarker development and also to develop strategies to overcome overt drug resistance for example by the use of combination therapies.

Dr. Helen M. Coley
Guest Editor

Manuscript Submission Information

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Published Papers (11 papers)

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Research

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Open AccessArticle Modulation of RAB7A Protein Expression Determines Resistance to Cisplatin through Late Endocytic Pathway Impairment and Extracellular Vesicular Secretion
Received: 9 November 2018 / Revised: 25 December 2018 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
Background: Cisplatin (CDDP) is widely used in treatment of cancer, yet patients often develop resistance with consequent therapeutical failure. In CDDP-resistant cells alterations of endocytosis and lysosomal functionality have been revealed, although their causes and contribution to therapy response are unclear. Methods: We
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Background: Cisplatin (CDDP) is widely used in treatment of cancer, yet patients often develop resistance with consequent therapeutical failure. In CDDP-resistant cells alterations of endocytosis and lysosomal functionality have been revealed, although their causes and contribution to therapy response are unclear. Methods: We investigated the role of RAB7A, a key regulator of late endocytic trafficking, in CDDP-resistance by comparing resistant and sensitive cells using western blotting, confocal microscopy and real time PCR. Modulation of RAB7A expression was performed by transfection and RNA interference, while CDDP sensitivity and intracellular accumulation were evaluated by viability assays and chemical approaches, respectively. Also extracellular vesicles were purified and analyzed. Finally, correlations between RAB7A and chemotherapy response was investigated in human patient samples. Results: We demonstrated that down-regulation of RAB7A characterizes the chemoresistant phenotype, and that RAB7A depletion increases CDDP-resistance while RAB7A overexpression decreases it. In addition, increased production of extracellular vesicles is modulated by RAB7A expression levels and correlates with reduction of CDDP intracellular accumulation. Conclusions: We demonstrated, for the first time, that RAB7A regulates CDDP resistance determining alterations in late endocytic trafficking and drug efflux through extracellular vesicles. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessArticle Use of Germline Genetic Variability for Prediction of Chemoresistance and Prognosis of Breast Cancer Patients
Cancers 2018, 10(12), 511; https://doi.org/10.3390/cancers10120511
Received: 5 November 2018 / Revised: 29 November 2018 / Accepted: 8 December 2018 / Published: 12 December 2018
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Abstract
The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509
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The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509 genes, selected from PharmGKB and Phenopedia, were sequenced using massive parallel sequencing in blood DNA from 105 breast cancer patients in the testing phase. In total, 18,245 variants were identified of which 2565 were novel variants (without rs number in dbSNP build 150) in the testing phase. Variants with major allele frequency over 0.05 were further prioritized for validation phase based on a newly developed decision tree. Using emerging in silico tools and pharmacogenomic databases for functional predictions and associations with response to cytotoxic therapy or disease-free survival of patients, 55 putative variants were identified and used for validation in 805 patients with clinical follow up using KASPTM technology. In conclusion, associations of rs2227291, rs2293194, and rs4376673 (located in ATP7A, KCNAB1, and DFFB genes, respectively) with response to neoadjuvant cytotoxic therapy and rs1801160 in DPYD with disease-free survival of patients treated with cytotoxic drugs were validated and should be further functionally characterized. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessArticle Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells
Cancers 2018, 10(11), 396; https://doi.org/10.3390/cancers10110396
Received: 11 September 2018 / Revised: 17 October 2018 / Accepted: 22 October 2018 / Published: 24 October 2018
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Abstract
The protein p53 protects the organism against carcinogenic events by the induction of cell cycle arrest and DNA repair program upon DNA damage. Virtually all cancers inactivate p53 either by mutations/deletions of the TP53 gene or by boosting negative regulation of p53 activity.
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The protein p53 protects the organism against carcinogenic events by the induction of cell cycle arrest and DNA repair program upon DNA damage. Virtually all cancers inactivate p53 either by mutations/deletions of the TP53 gene or by boosting negative regulation of p53 activity. The overexpression of MDM2 protein is one of the most common mechanisms utilized by p53wt cancers to keep p53 inactive. Inhibition of MDM2 action by its antagonists has proved its anticancer potential in vitro and is now tested in clinical trials. However, the prolonged treatment of p53wt cells with MDM2 antagonists leads to the development of secondary resistance, as shown first for Nutlin-3a, and later for three other small molecules. In the present study, we show that secondary resistance occurs also after treatment of p53wt cells with idasanutlin (RG7388, RO5503781), which is the only MDM2 antagonist that has passed phase II and entered phase III clinical trials, so far. Idasanutlin strongly activates p53, as evidenced by the induction of p21 expression and potent cell cycle arrest in all the three cell lines tested, i.e., MCF-7, U-2 OS, and SJSA-1. Notably, apoptosis was induced only in SJSA-1 cells, while MCF-7 and U-2 OS cells were able to restore the proliferation upon the removal of idasanutlin. Moreover, idasanutlin-treated U-2 OS cells could be cultured for long time periods in the presence of the drug. This prolonged treatment led to the generation of p53-mutated resistant cell populations. This resistance was generated de novo, as evidenced by the utilization of monoclonal U-2 OS subpopulations. Thus, although idasanutlin presents much improved activities compared to its precursor, it displays the similar weaknesses, which are limited elimination of cancer cells and the generation of p53-mutated drug-resistant subpopulations. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessArticle Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations upon Treatment with Temozolomide In Vitro and In Vivo
Cancers 2018, 10(10), 362; https://doi.org/10.3390/cancers10100362
Received: 8 August 2018 / Revised: 1 September 2018 / Accepted: 26 September 2018 / Published: 28 September 2018
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Abstract
The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly resistant to this drug. TMZ is
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The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly resistant to this drug. TMZ is in clinical use for melanoma, but objective response rates are low, even when TMZ is combined with O6-benzylguanine (O6BG), a potent MGMT inhibitor. We used in vitro and in vivo models of melanoma to characterize the early events leading to cellular TMZ resistance. Melanoma cell lines were exposed to a single treatment with TMZ, at physiologically relevant concentrations, in the absence or presence of O6BG. Surviving clones and mass cultures were analyzed by Western blot, colony formation assays, and DNA methylation studies. Mice with melanoma xenografts received TMZ treatment, and tumor tissue was analyzed by immunohistochemistry. We found that MGMT-negative melanoma cell cultures, before any drug treatment, already harbored a small fraction of MGMT-positive cells, which survived TMZ treatment and promptly became the dominant cell type within the surviving population. The MGMT-negative status in individual cells was not stable, as clonal selection of MGMT-negative cells again resulted in a mixed population harboring MGMT-positive, TMZ-resistant cells. Blocking the survival advantage of MGMT via the addition of O6BG still resulted in surviving clones, although at much lower frequency and independent of MGMT, and the resistance mechanism of these clones was based on a common lack of expression of MSH6, a key MMR enzyme. TMZ treatment of mice implanted with MGMT-negative melanoma cells resulted in effective tumor growth delay, but eventually tumor growth resumed, with tumor tissue having become MGMT positive. Altogether, these data reveal stochastic expression of MGMT as a pre-existing, key determinant of TMZ resistance in melanoma cell lines. Although MGMT activity can effectively be eliminated by pharmacologic intervention with O6BG, additional layers of TMZ resistance, although considerably rarer, are present as well and minimize the cytotoxic impact of TMZ/O6BG combination treatment. Our results provide rational explanations regarding clinical observations, where the TMZ/O6BG regimen has yielded mostly disappointing outcomes in melanoma patients. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessArticle miR-1246 Targets CCNG2 to Enhance Cancer Stemness and Chemoresistance in Oral Carcinomas
Cancers 2018, 10(8), 272; https://doi.org/10.3390/cancers10080272
Received: 13 July 2018 / Revised: 7 August 2018 / Accepted: 13 August 2018 / Published: 16 August 2018
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Abstract
MiRNAs have been recognized as crucial components in carcinogenesis, but whether miR-1246 affects the cancer stemness and drug resistance in oral squamous cell carcinoma (OSCC) has not been fully understood and its downstream targets still need to be unraveled. In the present work,
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MiRNAs have been recognized as crucial components in carcinogenesis, but whether miR-1246 affects the cancer stemness and drug resistance in oral squamous cell carcinoma (OSCC) has not been fully understood and its downstream targets still need to be unraveled. In the present work, we employed miRNAs RT-PCR analysis to evaluate the expression of miR-1246 in tumor tissues and oral cancer stem cells (OCSC). Stemness phenotypes, including self-renewal, migration, invasion, colony formation capacities, and in vivo oncogenicity of oral cancer cells following transfected with miR-1246 inhibitors or mimics were examined. Our results suggested that the expression level of miR-1246 was significantly upregulated in the tumor tissues and OCSC. Kaplan-Meier survival analysis of OSCC patients with high levels of miR-1246 had the worst survival rate compared to their low-expression counterparts. Inhibition of miR-1246 in OCSC significantly reduced the stemness hallmarks, while overexpression of miR-1246 enhanced these characteristics. Moreover, we showed that downregulation of miR-1246 decreased chemoresistance. In addition, we verified that miR-1246-inhibited CCNG2 contributed to the cancer stemness of OSCC. These results demonstrated the significance of miR-1246 in the regulation of OSCC stemness. Targeting miR-1246-CCNG2 axis may be beneficial to suppress cancer relapse and metastasis in OSCC patients. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessArticle TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727
Cancers 2018, 10(8), 254; https://doi.org/10.3390/cancers10080254
Received: 10 July 2018 / Revised: 26 July 2018 / Accepted: 27 July 2018 / Published: 31 July 2018
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Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are
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Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Review

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Open AccessReview Platinum Resistance in Ovarian Cancer: Role of DNA Repair
Cancers 2019, 11(1), 119; https://doi.org/10.3390/cancers11010119
Received: 5 November 2018 / Revised: 15 January 2019 / Accepted: 17 January 2019 / Published: 20 January 2019
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Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs.
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Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity. We analyzed the major DNA repair pathways potentially involved in drug resistance, detailing gene mutation, duplication or deletion as well as polymorphisms as potential biomarkers for drug resistance development. We dissected potential ways to overcome DNA repair-associated drug resistance thanks to the development of new combinations and/or drugs directly targeting DNA repair proteins or taking advantage of the vulnerability arising from DNA repair defects in EOCs. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessFeature PaperReview Transporter and Lysosomal Mediated (Multi)drug Resistance to Tyrosine Kinase Inhibitors and Potential Strategies to Overcome Resistance
Cancers 2018, 10(12), 503; https://doi.org/10.3390/cancers10120503
Received: 8 November 2018 / Revised: 29 November 2018 / Accepted: 4 December 2018 / Published: 10 December 2018
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Abstract
Tyrosine kinase inhibitors are a class of chemotherapeutic drugs that target specific protein kinases. These tyrosine kinase inhibitors constitute a relatively new class of drugs which target for instance Bcr-Abl, Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Despite
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Tyrosine kinase inhibitors are a class of chemotherapeutic drugs that target specific protein kinases. These tyrosine kinase inhibitors constitute a relatively new class of drugs which target for instance Bcr-Abl, Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Despite some initial successes, the overall therapeutic benefit of tyrosine kinase inhibitors in the clinic has been mixed. Next to mutations in the target, multidrug resistance is a major obstacle for which still no clinically effective strategies have been developed. Major mechanisms of multidrug resistance are mediated by drug efflux transporter proteins. Moreover, there is accumulating evidence that multidrug resistance can also be caused by lysosomal sequestration of drugs, effectively trapping tyrosine kinase inhibitors and preventing them from reaching their target. Lysosomal drug sequestration seems to work together with ATP-binding cassette transporters, increasing the capacity of lysosomes to mediate sequestration. Both membrane efflux transporter proteins and lysosomes present potential therapeutic targets that could reverse multidrug resistance and increase drug efficacy in combination therapy. This review describes both mechanisms and discusses a number of proposed strategies to circumvent or reverse tyrosine kinase inhibitor-related multidrug resistance. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessFeature PaperReview Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance
Cancers 2018, 10(12), 482; https://doi.org/10.3390/cancers10120482
Received: 22 October 2018 / Revised: 28 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
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Abstract
Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance.
[...] Read more.
Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessReview Chemoresistance and the Self-Maintaining Tumor Microenvironment
Cancers 2018, 10(12), 471; https://doi.org/10.3390/cancers10120471
Received: 8 November 2018 / Revised: 24 November 2018 / Accepted: 27 November 2018 / Published: 28 November 2018
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Abstract
The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the
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The progression of cancer is associated with alterations in the tumor microenvironment, including changes in extracellular matrix (ECM) composition, matrix rigidity, hypervascularization, hypoxia, and paracrine factors. One key malignant phenotype of cancer cells is their ability to resist chemotherapeutics, and elements of the ECM can promote chemoresistance in cancer cells through a variety of signaling pathways, inducing changes in gene expression and protein activity that allow resistance. Furthermore, the ECM is maintained as an environment that facilitates chemoresistance, since its constitution modulates the phenotype of cancer-associated cells, which themselves affect the microenvironment. In this review, we discuss how the properties of the tumor microenvironment promote chemoresistance in cancer cells, and the interplay between these external stimuli. We focus on both the response of cancer cells to the external environment, as well as the maintenance of the external environment, and how a chemoresistant phenotype emerges from the complex signaling network present. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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Open AccessReview Molecular Markers of Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Literature Review
Cancers 2018, 10(10), 376; https://doi.org/10.3390/cancers10100376
Received: 5 September 2018 / Revised: 1 October 2018 / Accepted: 8 October 2018 / Published: 10 October 2018
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Abstract
This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet
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This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet another challenge—that of preserving oral functions, which involves the use of multidisciplinary therapies, such as multiple chemotherapies (CT) and radiotherapy (RT). Designing personalized therapeutic options requires the study of genes involved in drug resistance. This review provides an overview of the molecules that have been linked to resistance to chemotherapy in HNSCC, including the family of ATP-binding cassette transporters (ABCs), nucleotide excision repair/base excision repair (NER/BER) enzymatic complexes (which act on nonspecific DNA lesions generated by gamma and ultraviolet radiation by cross-linking and forming intra/interchain chemical adducts), cisplatin (a chemotherapeutic agent that causes DNA damage and induces apoptosis, which is a paradox because its effectiveness is based on the integrity of the genes involved in apoptotic signaling pathways), and cetuximab, including a discussion of the genes involved in the cell cycle and the proliferation of possible markers that confer resistance to cetuximab. Full article
(This article belongs to the Special Issue Cancer Chemoresistance)
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