Bioinformatics and Experimental Validation for Identifying Biomarkers Associated with AMG510 (Sotorasib) Resistance
Peng Lin1, Wei Cheng1, Xin Qi1
1Key Laboratory of Marine Drugs, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Abstract:
The Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C mutation is prevalent in lung adenocarcinoma (LUAD), driving tumor progression and indicating a poor prognosis. While the FDA-approved AMG510 (Sotorasib) initially demonstrated efficacy in treating KRASG12C-mutated LUAD, resistance emerged within months. Data from AMG510 treatment-resistant LUAD (GSE204753) and single-cell datasets (GSE149655) were analyzed. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were used to explore enriched signaling pathways, nomogram models were constructed, and transcription factors predicting resistance biomarkers were predicted. CIBERSORT identified immune cell subpopulations, and their association with resistance biomarkers was assessed through single-cell analysis. AMG510-resistant LUAD cells (H358-AR) were constructed, and proliferative changes were evaluated using a CCK-8 assay. Key molecules for AMG510 resistance, including SLC2A1, TLE1, FAM83A, HMGA2, FBXO44, and MTRNR2L12, were recognized. These molecules impacted multiple signaling pathways and the tumor microenvironment and were co-regulated by various transcription factors. Single-cell analysis revealed a dampening effect on immune cell function, with associations with programmed cell death ligand 1 (PDL1) expression, cytokine factors, and failure factors. The findings indicate that these newly identified biomarkers are linked to the abnormal expression of PDL1 and have the potential to induce resistance through immunosuppression. These results highlight the need for further research and therapeutic intervention to address this issue effectively.
Insights
KRAS G12C-mutated lung adenocarcinoma (LUAD) initially responds to AMG510, but resistance develops. New biomarkers driving resistance through immunosuppression were identified, requiring further therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The KRAS G12C mutation is a key driver in lung adenocarcinoma (LUAD), associated with poor prognosis.
- AMG510 (Sotorasib) shows initial efficacy but acquired resistance is a significant clinical challenge.
Purpose of the Study:
- To identify molecular mechanisms and biomarkers associated with AMG510 resistance in KRAS G12C-mutated LUAD.
- To explore the impact of resistance mechanisms on the tumor microenvironment and immune cell function.
Main Methods:
- Analysis of gene expression data from AMG510-resistant LUAD and single-cell datasets.
- Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), CIBERSORT, and nomogram construction.
- In vitro validation using AMG510-resistant LUAD cell lines (H358-AR) and CCK-8 assays.
Main Results:
- Key molecules (SLC2A1, TLE1, FAM83A, HMGA2, FBXO44, MTRNR2L12) were identified as drivers of AMG510 resistance.
- These molecules influence multiple signaling pathways and the tumor microenvironment, regulated by transcription factors.
- Single-cell analysis revealed suppressed immune cell function linked to PDL1 expression and immunosuppression.
Conclusions:
- Newly identified biomarkers are associated with abnormal PDL1 expression and induce resistance via immunosuppression.
- These findings highlight potential therapeutic targets and the need for strategies to overcome AMG510 resistance in LUAD.
