对化疗药物反应的改变主要源于编码区内单点突变的增加以及与耐药机制有关的基因表达水平的失调。基于突变谱和表达水平的生物标志物的识别对于阐明药物反应改变的潜在机制和完善肿瘤学领域的组合治疗策略至关重要。利用全面的生物信息学分析，我们通过整合突变谱，研究了 8 个错配修复 (MMR) 基因对 23 种癌症类型（涵盖 7,500 多种肿瘤）总体生存的影响。在这些基因中，MSH6 成为最具预测性的生物标志物，其特征是显着的突变频率和升高的表达水平，这与较差的患者生存结果相关。湿实验室实验揭示了 MSH6 在调节药物反应改变中的影响。进行的细胞毒性测定表明，H460 非小肺癌细胞中 MSH6 的消耗增强了顺铂、卡铂和吉西他滨的疗效。通路分析进一步描绘了 MSH6 作为调节剂的参与，影响自噬的促生存和促死亡功能之间的微妙平衡。我们的研究阐明了 MSH6、自噬和顺铂疗效之间复杂的相互作用，强调 MSH6 作为克服顺铂耐药性的潜在治疗靶点。通过揭示 MSH6 抑制对自噬途径的调节，我们的研究结果为通过靶向干预增强顺铂癌症治疗功效的新方法提供了见解。版权所有 © 2024。由 Elsevier B.V. 出版。

The altered response to chemotherapeutic agents predominantly stems from heightened single-point mutations within coding regions and dysregulated expression levels of genes implicated in drug resistance mechanisms. The identification of biomarkers based on mutation profiles and expression levels is pivotal for elucidating the underlying mechanisms of altered drug responses and for refining combinatorial therapeutic strategies in the field of oncology. Utilizing comprehensive bioinformatic analyses, we investigated the impact of eight mismatch repair (MMR) genes on overall survival across 23 cancer types, encompassing more than 7,500 tumors, by integrating their mutation profiles. Among these genes, MSH6 emerged as the most predictive biomarker, characterized by a pronounced mutation frequency and elevated expression levels, which correlated with poorer patient survival outcomes. The wet lab experiments disclosed the impact of MSH6 in mediating altered drug responses. Cytotoxic assays conducted revealed that the depletion of MSH6 in H460 non-small lung cancer cells augmented the efficacy of cisplatin, carboplatin, and gemcitabine. Pathway analyses further delineated the involvement of MSH6 as a modulator, influencing the delicate equilibrium between the pro-survival and pro-death functions of autophagy. Our study elucidates the intricate interplay between MSH6, autophagy, and cisplatin efficacy, highlighting MSH6 as a potential therapeutic target to overcome cisplatin resistance. By revealing the modulation of autophagy pathways by MSH6 inhibition, our findings offer insights into novel approaches for enhancing the efficacy of cisplatin-based cancer therapy through targeted interventions.Copyright © 2024. Published by Elsevier B.V.