KRAS is among the most frequently mutated oncogenes across all human cancers. Targeting KRAS-mutant cancers either directly or at the effector level has so far failed in the clinic, with adoptive responses and toxicities being the major limiting factors. Nevertheless, direct targeting of the mutant KRAS-G12C allele has shown promising results in early clinical trials. BI-3406 is an inhibitor of the interaction between KRAS and its Guanine Nucleotide Exchange Factor (GEF) SOS1. The efficient loading of both mutant as well as wild-type KRAS with GTP depends on SOS1. We present the activity of the potent and selective SOS1::KRAS inhibitor BI-3406 in monotherapy and combinations in a different presentation at this meeting (Marco H Hofmann et al.). In this work, we focus on the characterization of suitable pharmacodynamic biomarkers in pre-clinical studies. Analysis of the well-studied RAS-MAPK effector p-ERK demonstrates BI-3406 treatment induced modulation in the majority of tested cell lines, independent of their KRAS mutation status. Interestingly, the effects on p-AKT levels, linked to PI3K signaling, were much less pronounced, indicating that the MAPK pathway is the major effector pathway of mutant KRAS singnaling. Confirmatory results were obtained from a technically independent and orthogonal platform. These findings are supported by a genome-wide transcriptome analysis, which revealed well established feedback regulators and p-ERK targets such as DUSP6, EGR1, or ETV5 as robust pharmacodynamic biomarkers in response to SOS1::KRAS inhibitor treatment. Importantly, we also compare biomarker responses of SOS1::KRAS inhibition to direct KRAS-G12C inhibition. In summary, these transcript-based biomarkers add value over conventional downstream signaling protein biomarkers such as p-ERK and will be implemented in future clinical trials.

Citation Format: Daniel Gerlach, Fabio Savarese, Marco H Hofmann, Francesca Trapani, Michael Gmachl, Dana-Adriana Botesteanu, Jürgen Ramharter, Heribert Arnhof, Norbert Schweifer, Darryl B McConnell, Norbert Kraut. Evaluation of phosphoprotein- and transcript-based pharmacodynamic biomarkers in pre-clinical studies of the novel 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 A030. doi:10.1158/1535-7163.TARG-19-A030

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.