Related Experiment Video
Updated: Aug 8, 2026
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
Potential biomarkers uncovered by bioinformatics analysis in sotorasib resistant-pancreatic ductal adenocarcinoma
Prasanna Srinivasan Ramalingam1, Annadurai Priyadharshini2, Isaac Arnold Emerson2
1Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
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.
Insights
Resistance to KRAS G12C inhibitor sotorasib is a growing problem in pancreatic cancer. This study identifies ribosomal protein S3 (RPS3) as a key biomarker driving sotorasib resistance by evading apoptosis. Combination therapy may overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Mutant KRAS drives tumorigenesis in lung, colon, and pancreatic cancers.
- KRAS mutants were considered undruggable until the development of the KRAS G12C inhibitor sotorasib (AMG 510).
- Emerging resistance to sotorasib in non-small-cell lung cancer and pancreatic ductal adenocarcinoma necessitates understanding resistance mechanisms.
Purpose of the Study:
- To identify crucial biomarkers driving sotorasib (AMG 510) resistance in KRAS G12C-mutant pancreatic ductal adenocarcinoma cells.
- To analyze gene expression profiles and protein-protein interactions to uncover resistance mechanisms.
Main Methods:
- RNA-sequencing (RNA-seq) data analysis of MIA-PaCa2 cells.
- Differential gene expression (DEG) analysis using the limma package.
- Protein-protein interaction (PPI) network analysis using the STRING database and hub gene identification.
Main Results:
- Differential gene expression and PPI analysis identified potential biomarkers for sotorasib resistance.
- Enrichment and survival analyses revealed ribosomal protein S3 (RPS3) as a crucial biomarker in KRAS G12C-mutant pancreatic ductal adenocarcinoma cells resistant to AMG 510.
Conclusions:
- RPS3 is a critical biomarker for sotorasib resistance, mediating resistance through MDM2/4 interaction to evade apoptosis.
- Combinatorial therapy with sotorasib and RNA polymerase I inhibitors presents a potential strategy to overcome resistance, warranting further in vitro and in vivo investigation.
