Reference Detail

Ref Type

Journal Article

PMID

(27820802)

Authors

Spencer-Smith R, Koide A, Zhou Y, Eguchi RR, Sha F, Gajwani P, Santana D, Gupta A, Jacobs M, Herrero-Garcia E, Cobbert J, Lavoie H, Smith M, Rajakulendran T, Dowdell E, Okur MN, Dementieva I, Sicheri F, Therrien M, Hancock JF, Ikura M, Koide S, O'Bryan JP

Title

Inhibition of RAS function through targeting an allosteric regulatory site.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature chemical biology	13	1	2017 Jan	62-68	Nat Chem Biol

URL

Abstract Text

RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the α4-β6-α5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the α4-β6-α5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

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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
NS1	NS1	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NS1			HRAS Inhibitor 1 KRAS Inhibitor 18	NS1 is a synthetic monobody that binds to GTP and GDP states of HRAS and KRAS, thereby inhibiting RAS dimerization and subsequent RAF activity, which may result in inhibition of cell transformation (PMID: 27820802, PMID: 29072601).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
HRAS	R135A	missense	unknown	HRAS R135A does not lie within any known functional domains of the Hras protein (UniProt.org). R135A results in impaired GTP-HRAS downstream signaling when combined with R128A (PMID: 18273062), and is associated with resistance to NS1 (PMID: 27820802), but has not been fully biochemically characterized and therefore, its effect on Hras protein function is unknown.	Y
HRAS	R135K	missense	unknown	HRAS R135K does not lie within any known functional domains of the Hras protein (UniProt.org). R135K is predicted to disrupt the allosteric interaction within Hras by molecular dynamics simulation (PMID: 29072601), and results in decreased NS1 binding in the context of HRAS G12C, resulting in resistance to NS1, in cultured cells (PMID: 27820802) and leads to loss of binding to NS1 in cultured cells in another study (PMID: 36252024), but has not been fully biochemically characterized and therefore, its effect on Hras protein function is unknown.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
HRAS Q61L	Advanced Solid Tumor	sensitive	NS1	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing HRAS Q61L demonstrated sensitivity to NS1, resulting in inhibition of Mapk and Akt signaling and cell transformation in culture (PMID: 27820802).	27820802
HRAS G12V HRAS R135K	Advanced Solid Tumor	resistant	NS1	Preclinical	Actionable	In a preclinical study, introducing HRAS R135K mutation in transformed cells expressing HRAS G12V resulted in reduced binding of Hras to NS1, leading to resistance to Mapk pathway inhibition in cell culture (PMID: 27820802).	27820802
HRAS G12V HRAS R135A	Advanced Solid Tumor	resistant	NS1	Preclinical	Actionable	In a preclinical study, introducing HRAS R135A mutation in transformed cells expressing HRAS G12V resulted in reduced binding of Hras to NS1, leading to resistance to Mapk pathway inhibition in cell culture (PMID: 27820802).	27820802
NRAS G12D	Advanced Solid Tumor	no benefit	NS1	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NRAS G12D did not respond to treatment with NS1 in culture, resulting in sustained downstream signaling and cell transformation (PMID: 27820802).	27820802