KRAS^G12C-independent feedback activation of wild-type RAS constrains KRAS^G12C inhibitor efficacy.

ABSTRACT: Although KRAS has long been considered undruggable, direct KRAS^G12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type RAS, as opposed to a shift in KRAS^G12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRAS^G12C-independent manner. Moreover, multiple receptor tyrosine kinases (RTKs) can drive feedback reactivation, potentially nec

SUBMITTER: Ryan MB 

PROVIDER: S-EPMC9809542 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature