The KRAS^G12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients.

ABSTRACT: Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRAS^G12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRAS^G12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRAS^G12C-positive cell line- and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRAS^G12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor acti

SUBMITTER: Hallin J 

PROVIDER: S-EPMC6954325 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature