adagrasib
Overview
Adagrasib (MRTX849) is a covalent, irreversible small-molecule inhibitor targeting KRASG12C. It selectively binds the mutant cysteine at position 12, locking KRAS in its inactive GDP-bound state. Approved by the FDA for KRASG12C-mutant non-small cell lung cancer and, in combination with cetuximab, for KRASG12C-mutant colorectal cancer.
Evidence in the corpus
- Used in combination with cetuximab (anti-EGFR antibody) for KRASG12C-mutant colorectal cancer (n=8 patients: adagrasib + cetuximab); response rate approximately 40%. Resistance is highly heterogeneous with multiple low-frequency alterations co-occurring; KRASG12C amplification is the only resistance alteration that increases steadily in proportion to tumor markers PMID:36355783
Resistance mechanisms
- Heterogeneous acquired resistance mechanisms: KRAS switch mutations, NRAS mutations (Q61K/R), BRAF mutations and fusions (SEC23A-BRAF), MAP2K1 mutations (R47_E62delinsQ), MET amplification/fusion, RET fusion, EGFR mutations, MYC amplification — all at low VAF PMID:36355783
- KRASG12C amplification as a recurrent resistance mechanism induces oncogene-induced senescence upon drug withdrawal, with elevated mTOR signaling protecting from apoptosis PMID:36355783
Cancer types (linked)
- COADREAD — KRASG12C-mutant colorectal cancer treated with adagrasib + cetuximab combination
Sources
This page was processed by crosslinker on 2026-05-06.