Reference Detail

Ref Type Journal Article
PMID (27104980)
Authors Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, Baker SJ, Cosenza SC, Basu I, Gupta YK, Reddy MV, Ueno L, Hart JR, Vogt PK, Mulholland D, Guha C, Aggarwal AK, Reddy EP
Title A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling.
Journal Cell
Vol 165
Issue 3
Date 2016 Apr 21
URL
Abstract Text Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

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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
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
KRAS G13D colorectal cancer sensitive Rigosertib Preclinical - Cell line xenograft Actionable In a preclinical study, Estybon (rigosertib) inhibited Mek/Erk signaling and tumor growth in cell line xenograft models of colorectal cancer harboring KRAS G13D (PMID: 27104980). 27104980
KRAS G12S lung cancer sensitive Rigosertib Preclinical - Cell line xenograft Actionable In a preclinical study, Estybon (rigosertib) inhibited Mek/Erk signaling and tumor growth in cell line xenograft models of lung cancer harboring KRAS G12S (PMID: 27104980). 27104980
KRAS G12D pancreatic cancer sensitive Rigosertib Preclinical Actionable In a preclinical study, Estybon (rigosertib) inhibited tumorigenesis in transgenic animal model of pancreatic cancer driven by KRAS G12D (PMID: 27104980). 27104980
HRAS G12V Advanced Solid Tumor sensitive Rigosertib Preclinical - Cell culture Actionable In a preclinical study, Estybon (rigosertib) inhibited oncogenic transformation in fibroblast cells over-expressing HRAS G12V in culture (PMID: 27104980). 27104980