Reference Detail

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, Böttcher 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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	11	1	2021 Jan	142-157	Cancer Discov

URL

Abstract Text

KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success because of 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. SIGNIFICANCE: To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D. See related commentary by Zhao et al., p. 17 . This article is highlighted in the In This Issue feature, p. 1 .

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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
BI-3406	BI-3406	5	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BI-3406		HY-125817\|EX-A3418\|BI3406\|BI 3406	SOS1 Inhibitor 16	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 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
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
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