Identification and functional characterization of potential biomarkers in cisplatin resistance through bioinformatic analyses
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Abstract
Platinum-based chemotherapies, particularly cisplatin, are often limited by the emergence ofdrug resistance, driven not only by genetic alterations in DNA repair pathways but also byclinical factors such as patient age, race, gender, metastasis status, and tumor stage. To addressthese challenges, we performed integrative bioinformatics and experimental analyses acrossmore than 7,500 tumors spanning 23 cancer types, aiming to identify key genetic determinantsof chemoresistance.
Through comprehensive mutation profiling and overall survival analyses of genes involved inbase excision repair (BER), mismatch repair (MMR), and double-strand break (DSB) repairpathways, we identified PARP3, MSH6 and ATM as candidate predictive biomarkers.Functional studies using CRISPR/Cas9-and shRNA-mediated gene knockdown revealed thatsilencing these genes significantly increased cisplatin sensitivity in cancer cell lines.
Mechanistic investigations further showed that PARP3 loss disrupted PDGF and G protein-coupled receptor (GPCRs) signalling pathways, enhancing drug efficacy. MSH6depletionshifted the balance of autophagy from pro-survival to pro-death, sensitizing cells to cisplatin.In parallel,ATMknockout induced oxidative stress-mediated senescence via suppression ofNRF2signaling.
Collectively, our findings identifyMSH6,ATM, andPARP3as promising therapeutic targetsfor overcoming chemoresistance. The discovery of their associations with previouslyuncharacterized signalling pathways underscores their clinical and biological relevance. Byintegrating mutational landscapes with functional vulnerabilities, this study provides aconceptual framework for the development of personalized combination therapies tailored tothe molecular profile of individual tumors, ultimately offering innovative strategies to enhancetreatment efficacy in oncology.