KRAS G12C mutation is now a targetable oncogenic driver. Which drug specifically targets this mutation and what is its unique mechanism?

• A Adagrasib — a non-covalent competitive inhibitor of the GTP-binding site of all KRAS mutants including G12C, G12D and G12V
• B Trametinib — a MEK1/2 inhibitor that blocks downstream MAPK signalling from all KRAS-mutant cancers including G12C
• C Cetuximab — an EGFR monoclonal antibody that is effective in KRAS G12C-mutant colorectal cancer due to its unique wild-type KRAS selectivity
• D Sotorasib — a covalent irreversible inhibitor that specifically alkylates the mutant cysteine-12 residue, locking KRAS G12C in the inactive GDP-bound state ✓

Explanation

Sotorasib (AMG 510) was the first FDA-approved KRAS inhibitor, targeting the specific G12C mutation. KRAS G12C substitutes the normal glycine-12 with cysteine. Sotorasib irreversibly forms a covalent bond with the mutant cysteine-12 (exploiting its unique nucleophilic thiol group absent in wild-type KRAS) within a pocket (Switch II Pocket, S-IIP) that exists only in the GDP-bound (inactive) form of the protein. This locks KRAS G12C permanently in the inactive GDP-bound state, preventing SOS1-mediated GTP exchange and downstream RAS-MAPK signalling. Wild-type KRAS and other KRAS mutations (G12D, G12V) lack cysteine-12 and are therefore not affected. Adagrasib is also a covalent KRAS G12C inhibitor but with additional properties (CNS penetration, ability to re-inhibit proteins that have re-bound GDP after initial dissociation).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.