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Ref Type Journal Article
PMID (29720559)
Authors Kauke MJ, Tisdale AW, Kelly RL, Braun CJ, Hemann MT, Wittrup KD
Title A Raf-Competitive K-Ras Binder Can Fail to Functionally Antagonize Signaling.
Journal Molecular cancer therapeutics
Vol 17
Issue 8
Date 2018 08
URL
Abstract Text Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines. Through lentiviral transduction, we generated cell lines that constitutively or through induction with doxycycline express R11.1.6 or a control protein YW1 and show specific binding by R11.1.6 to endogenous Ras through microscopy and co-immunoprecipitation experiments. Genetically encoded intracellular expression of this high-affinity Ras antagonist, however, fails to measurably disrupt signaling through either the MAPK or PI3K pathway. Consistently, cellular proliferation was unaffected as well. To understand this lack of signaling inhibition, we quantified the number of molecules of R11.1.6 expressed by the inducible cell lines and developed a simple mathematical model describing the competitive binding of Ras by R11.1.6 and Raf. This model supports a potential mechanism for the lack of biological effects that we observed, suggesting stoichiometric and thermodynamic barriers that should be overcome in pharmacologic efforts to directly compete with downstream effector proteins localized to membranes at very high effective concentrations. Mol Cancer Ther; 17(8); 1773-80. ©2018 AACR.

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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
R11.1.6 KRAS Inhibitor 6 R11.1.6 is a protein antagonist that preferentially binds KRAS G12D, potentially resulting in inhibition of downstream Ras signaling (PMID: 28724936, PMID: 29720559).
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
Unknown unknown colorectal cancer not applicable R11.1.6 Preclinical - Cell culture Actionable In a preclinical study, R11.1.6 treatment did not inhibit cell proliferation and colony formation in a colorectal cancer cell line in culture (PMID: 29720559). 29720559
Unknown unknown colorectal cancer not applicable R11.1.6 + Wortmannin Preclinical - Cell culture Actionable In a preclinical study, R11.1.6 and Wortmannin combination therapy did not inhibit cell proliferation in a colorectal cancer cell line in culture (PMID: 29720559). 29720559
Unknown unknown skin squamous cell carcinoma not applicable R11.1.6 Preclinical - Cell culture Actionable In a preclinical study, R11.1.6 treatment did not inhibit colony formation in a skin squamous cell carcinoma cell line in culture (PMID: 29720559). 29720559
Unknown unknown colorectal cancer not applicable R11.1.6 + ZSTK474 Preclinical - Cell culture Actionable In a preclinical study, R11.1.6 and ZSTK474 combination therapy did not inhibit cell proliferation in a colorectal cancer cell line in culture (PMID: 29720559). 29720559