Frontiers in Medicine (Jun 2023)

Potential biomarkers uncovered by bioinformatics analysis in sotorasib resistant-pancreatic ductal adenocarcinoma

  • Prasanna Srinivasan Ramalingam,
  • Annadurai Priyadharshini,
  • Isaac Arnold Emerson,
  • Sivakumar Arumugam

DOI
https://doi.org/10.3389/fmed.2023.1107128
Journal volume & issue
Vol. 10

Abstract

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BackgroundMutant 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.MethodsIn 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.ResultsFurthermore, 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.ConclusionFinally, 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 in vitro and in vivo settings in near future.

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