Weiss, Lorthiois, and colleagues developed JDQ443, a structurally unique, potent, and covalent KRAS G12C inhibitor capable of inhibiting downstream signaling and proliferation, including in KRAS G12C-mutant cells with secondary KRAS mutations associated with KRAS G12C inhibitor resistance, and with antitumor activity in preclinical models as both a monotherapy and in combination with inhibitors of SHP2, MEK1/2, and CDK4/6. Several covalent inhibitors targeting this mutation have entered clinical development and have demonstrated antitumor activity however, acquired resistance has emerged, and combination strategies have been suggested.
Mutations in KRAS span many cancer types and had been considered undruggable until the development of small-molecule inhibitors of the KRAS G12C mutant protein.
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