SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS^G12D inhibitor in KRAS LUAD.

ABSTRACT: We evaluated the in vivo therapeutic efficacy and tolerability of BI-3406-mediated pharmacological inhibition of SOS1 in comparison to genetic ablation of this universal Ras-GEF in various KRAS-dependent experimental tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2^KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. Allograft assays using different KRAS^mut cell lines showed that treatment with BI-3406 impaired RAS activation and RAS downstream signaling and decreased tumor burden and disease progression as a result of both tumor-intrinsic and -extrinsic therapeutic effects of the drug. Consistent with prior genetic e

SUBMITTER: Baltanas FC 

PROVIDER: S-EPMC11929440 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature