Ramalingam Prasanna Srinivasan, Priyadharshini Annadurai, Emerson Isaac Arnold, Arumugam Sivakumar
Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
Bioinformatics Programming Laboratory, Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Front Med (Lausanne). 2023 Jun 15;10:1107128. doi: 10.3389/fmed.2023.1107128. eCollection 2023.
Mutant KRAS-induced tumorigenesis is prevalent in lung, colon, and pancreatic ductal adenocarcinomas. For the past 3 decades, KRAS mutants seem undruggable due to their high-affinity GTP-binding pocket and smooth surface. Structure-based drug design helped in the design and development of first-in-class KRAS G12C inhibitor sotorasib (AMG 510) which was then approved by the FDA. Recent reports state that AMG 510 is becoming resistant in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma patients, and the crucial drivers involved in this resistance mechanism are unknown.
In recent years, RNA-sequencing (RNA-seq) data analysis has become a functional tool for profiling gene expression. The present study was designed to find the crucial biomarkers involved in the sotorasib (AMG 510) resistance in KRAS G12C-mutant MIA-PaCa2 cell pancreatic ductal adenocarcinoma cells. Initially, the GSE dataset was retrieved from NCBI GEO, pre-processed, and then subjected to differentially expressed gene (DEG) analysis using the limma package. Then the identified DEGs were subjected to protein-protein interaction (PPI) using the STRING database, followed by cluster analysis and hub gene analysis, which resulted in the identification of probable markers.
Furthermore, the enrichment and survival analysis revealed that the small unit ribosomal protein (RP) RPS3 is the crucial biomarker of the AMG 510 resistance in KRAS G12C-mutant MIA-PaCa2 cell pancreatic ductal adenocarcinoma cells.
Finally, we conclude that RPS3 is a crucial biomarker in sotorasib resistance which evades apoptosis by MDM2/4 interaction. We also suggest that the combinatorial treatment of sotorasib and RNA polymerase I machinery inhibitors could be a possible strategy to overcome resistance and should be studied in and settings in near future.
突变型KRAS诱导的肿瘤发生在肺癌、结肠癌和胰腺导管腺癌中很常见。在过去30年里，KRAS突变体因其高亲和力的GTP结合口袋和平滑表面而似乎难以成药。基于结构的药物设计有助于设计和开发首个KRAS G12C抑制剂索托拉西布（AMG 510），该药物随后获得了美国食品药品监督管理局（FDA）的批准。最近的报告指出，AMG 510在非小细胞肺癌（NSCLC）、胰腺导管腺癌（PDAC）和肺腺癌患者中正在产生耐药性，而这种耐药机制中涉及的关键驱动因素尚不清楚。
近年来，RNA测序（RNA-seq）数据分析已成为分析基因表达的一种功能工具。本研究旨在寻找KRAS G12C突变的MIA-PaCa2细胞胰腺导管腺癌细胞中与索托拉西布（AMG 510）耐药相关的关键生物标志物。最初，从NCBI基因表达综合数据库（GEO）中检索GSE数据集，进行预处理，然后使用limma软件包进行差异表达基因（DEG）分析。然后，使用STRING数据库对鉴定出的DEG进行蛋白质-蛋白质相互作用（PPI）分析，随后进行聚类分析和枢纽基因分析，从而确定可能的标志物。
此外，富集分析和生存分析表明，小亚基核糖体蛋白（RP）RPS3是KRAS G12C突变的MIA-PaCa2细胞胰腺导管腺癌细胞中AMG 510耐药的关键生物标志物。
最后，我们得出结论，RPS3是索托拉西布耐药中的关键生物标志物，它通过MDM2/4相互作用逃避细胞凋亡。我们还建议，索托拉西布与RNA聚合酶I机制抑制剂的联合治疗可能是克服耐药性的一种策略，应在不久的将来在体内和体外环境中进行研究。
