Abstract C133: Effective targeting of KRAS-driven tumors by the first-in-class, orally bioavailable SOS1::KRAS inhibitor BI-3406

Abstract

Abstract KRAS is the most frequently mutated oncogene with high prevalence in pancreatic, colorectal, and non-small cell lung cancers. KRAS signaling is tightly regulated and release of negative feedback pathways have limited the clinical efficacy of inhibitors of the downstream MAPK signaling in the KRAS mutant context. Here we report the discovery of BI-3406, a highly potent and selective, first-in-class, orally bioavailable SOS1::KRAS inhibitor that binds to the catalytic domain of the guanine exchange factor SOS1 thereby preventing the interaction with KRAS-GDP. In KRAS-dependent cancers, BI 3406 potently reduces the formation of GTP-loaded KRAS, and inhibits MAPK pathway signaling. Down-modulation of this signaling cascade by BI-3406 in KRAS G12 or G13 mutant cells results in a cytostatic effect. In monotherapy, the observed pathway modulation translates into marked anti-tumor efficacy in KRAS mutant xenografts. BI-3406 blocks the negative feedback induced by MAPK inhibition and consequently sensitizes KRAS-dependent cancers to MEK inhibitor treatment resulting in complete blockade of the pathway, which translates into tumor regression in vivo. Collectively, our data suggest that SOS1 inhibition is a promising therapeutic strategy to treat KRAS dependent cancers in combination with MEK inhibition, with the aim to deliver meaningful survival benefits for cancer patients. Citation Format: Marco H Hofmann, Michael Gmachl, Jürgen Ramharter, Fabio Savarese, Michael P Sanderson, Daniel Gerlach, Francesca Trapani, Dana-Adriana Botesteanu, Dirk Kessler, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Renate Schnitzer, Christiane Kofink, Heinz Stadtmueller, Tobias Wunberg, Jonathan C. O’Connell, Rachel L Mendes, David Richard, Adrian S Saldanha, Juergen Moll, Mark Pearson, Darryl B McConnell, Norbert Kraut. Effective targeting of KRAS-driven tumors by the first-in-class, orally bioavailable SOS1::KRAS inhibitor BI-3406 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C133. doi:10.1158/1535-7163.TARG-19-C133