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Ref Type Journal Article
PMID (32816843)
Authors Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, Sanderson MP, Kessler D, Trapani F, Arnhof H, Rumpel K, Botesteanu DA, Ettmayer P, Gerstberger T, Kofink C, Wunberg T, Zoephel A, Fu SC, Teh JL, Bottcher J, Pototschnig N, Schachinger F, Schipany K, Lieb S, Vellano CP, O'Connell JC, Mendes RL, Moll J, Petronczki M, Heffernan TP, Pearson M, McConnell DB, Kraut N
Title BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition.
Journal Cancer discovery
Vol
Issue
Date 2020 Aug 19
URL
Abstract Text KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
BI-3406 HY-125817|EX-A3418|BI3406|BI 3406 KRAS Inhibitor 8 BI-3406 binds to SOS1 thus prevents SOS1 interaction with Kras-GDP, resulting in inhibition of Kras downstream signaling and potential inhibition of tumor cell growth (AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Oct 2019, Abstract PL06-01, PMID: 32816843).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF T119S BRAF V600E colorectal cancer predicted - resistant BI-3406 Preclinical - Cell culture Actionable In a preclinical study, BI-3406 treatment failed to inhibit growth of colorectal cancer cells harboring BRAF V600E and BRAF T119S in culture (PMID: 32816843). 32816843
BRAF V600E melanoma predicted - resistant BI-3406 Preclinical - Cell line xenograft Actionable In a preclinical study, BI-3406 treatment failed to inhibit growth of KRAS wild-type melanoma cells harboring BRAF V600E in culture and in cell line xenograft models (PMID: 32816843). 32816843
NRAS Q61K lung non-small cell carcinoma predicted - resistant BI-3406 Preclinical - Cell culture Actionable In a preclinical study, BI-3406 treatment failed to inhibit growth of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 32816843). 32816843
NRAS G12D ovarian cancer predicted - resistant BI-3406 Preclinical - Cell culture Actionable In a preclinical study, BI-3406 treatment failed to inhibit growth of ovarian cancer cells harboring NRAS G12D in culture (PMID: 32816843). 32816843
BRAF V600E colorectal cancer predicted - resistant BI-3406 Preclinical - Cell culture Actionable In a preclinical study, BI-3406 treatment failed to inhibit growth of colorectal cancer cells harboring BRAF V600E in culture (PMID: 32816843). 32816843