Diverse alterations associated with resistance to KRAS(G12C) inhibition.

ABSTRACT: Inactive state-selective KRAS(G12C) inhibitors^1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer⁹. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G1

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC8887821 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature