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

Prasanna Srinivasan Ramalingam; Annadurai Priyadharshini; Isaac Arnold Emerson; Sivakumar Arumugam

doi:10.3389/fmed.2023.1107128

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

Front Med (Lausanne). 2023 Jun 15:10:1107128. doi: 10.3389/fmed.2023.1107128. eCollection 2023.

Authors

Prasanna Srinivasan Ramalingam¹, Annadurai Priyadharshini², Isaac Arnold Emerson², Sivakumar Arumugam¹

Affiliations

¹ Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
² Bioinformatics Programming Laboratory, Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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 in vitro and in vivo settings in near future.

Keywords: KRAS G12C inhibitor; pancreatic ductal adenocarcinoma; precision medicine; resistance; ribosomal proteins; sotorasib.

Grants and funding

The authors thank Vellore Institute of Technology, Vellore for providing ‘VIT SEED Grant-RGEMS Fund (SG20220095)' for carrying out this research work.