SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma.

ABSTRACT: The clinical effectiveness of KRASG12C inhibitors (G12Ci) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. Here, we identified targeting proximal receptor tyrosine kinase signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment. SOS1i enhanced the efficacy of G12Ci and limited rebound receptor tyrosine kinase/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. G12Ci drug-tolerant persister (DTP) cells showed up to a 3-fold enrichment of tumor-initiating cells (TIC), suggestive of a sanctuary population of G12Ci-resistant cells. SOS1i resensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tu

SUBMITTER: Daley BR 

PROVIDER: S-EPMC11695159 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature