sotorasib
Overview
Sotorasib (AMG 510) is a covalent, irreversible small-molecule inhibitor targeting KRASG12C. It binds the mutant cysteine at position 12 and locks KRAS in its inactive GDP-bound state, thereby blocking oncogenic RAS signaling. Approved by the FDA for KRASG12C-mutant non-small cell lung cancer.
Evidence in the corpus
- Used in combination with cetuximab or panitumumab (anti-EGFR antibodies) for KRASG12C-mutant colorectal cancer (n=4 patients: sotorasib + panitumumab); response rate approximately 27% for sotorasib + panitumumab. KRASG12C amplification identified as a recurrent acquired resistance mechanism, tracking with tumor markers; mTOR inhibition (AZD8055) proposed as a senolytic strategy after drug withdrawal PMID:36355783
Resistance mechanisms
- KRASG12C amplification (>20 copies by FISH) drives oncogene-induced senescence upon drug withdrawal in colorectal cancer, creating mTOR-dependent vulnerability PMID:36355783
- Heterogeneous resistance alterations including KRAS switch mutations (G12A/D/F/L/R/S/V), NRAS mutations, BRAF mutations/fusions, MAP2K1 mutations, MET amplification/fusion, RET fusion, EGFR mutations, and MYC amplification — all at low VAF (one tenth to one hundredth of baseline) PMID:36355783
Cancer types (linked)
- COADREAD — KRASG12C-mutant colorectal cancer treated with sotorasib + panitumumab combination
Sources
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