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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 Nature chemical biology
Vol 13
Issue 1
Date 2017 Jan
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 8 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 is associated with resistance to NS1 (PMID: 27820802), but has not been 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
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
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