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Ref Type Journal Article
PMID (31257072)
Authors Fedoriw A, Rajapurkar SR, O'Brien S, Gerhart SV, Mitchell LH, Adams ND, Rioux N, Lingaraj T, Ribich SA, Pappalardi MB, Shah N, Laraio J, Liu Y, Butticello M, Carpenter CL, Creasy C, Korenchuk S, McCabe MT, McHugh CF, Nagarajan R, Wagner C, Zappacosta F, Annan R, Concha NO, Thomas RA, Hart TK, Smith JJ, Copeland RA, Moyer MP, Campbell J, Stickland K, Mills J, Jacques-O'Hagan S, Allain C, Johnston D, Raimondi A, Porter Scott M, Waters N, Swinger K, Boriack-Sjodin A, Riera T, Shapiro G, Chesworth R, Prinjha RK, Kruger RG, Barbash O, Mohammad HP
Title Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.
Journal Cancer cell
Vol 36
Issue 1
Date 2019 Jul 08
URL
Abstract Text Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

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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
GSK3368715 EPZ019997 GSK3368715 (EPZ019997) inhibits members of the type I PRMT family, which potentially in decreased tumor growth (PMID: 31257072).
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 lymphoma not applicable GSK3368715 Preclinical - Cell culture Actionable In a preclinical study, GSK3368715 inhibited growth of lymphoma cell lines in culture, and demonstrated cytotoxicity in 56% of cell lines tested (PMID: 31257072). 31257072
Unknown unknown clear cell renal cell carcinoma not applicable GSK3368715 Preclinical - Cell culture Actionable In a preclinical study, GSK3368715 inhibited tumor growth in a clear cell renal cell carcinoma xenograft model (PMID: 31257072). 31257072
Unknown unknown triple-receptor negative breast cancer not applicable GSK3368715 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK3368715 inhibited tumor growth in a triple-negative breast cancer cell line xenograft model (PMID: 31257072). 31257072
Unknown unknown diffuse large B-cell lymphoma not applicable GSK3368715 Preclinical - Patient cell culture Actionable In a preclinical study, GSK3368715 treatment inhibited growth of a diffuse large B-cell lymphoma (DLBCL) cell line in culture and inhibited tumor growth in xenograft models, and inhibited growth of patient-derived DLBCL cells in culture PMID: 31257072). 31257072
Unknown unknown lung non-small cell carcinoma not applicable GSK3368715 Preclinical - Cell culture Actionable In a preclinical study, GSK3368715 inhibited growth of non-small cell lung cancer cell lines in culture, and demonstrated cytotoxicity in 17% of cell lines tested (PMID: 31257072). 31257072
Unknown unknown pancreatic adenocarcinoma not applicable GSK3203591 + GSK3368715 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of GSK3203591 and GSK3368715 inhibited tumor growth in a pancreatic adenocarcinoma cell line xenograft model, demonstrating increased efficacy over either agent alone (PMID: 31257072). 31257072
Unknown unknown diffuse large B-cell lymphoma not applicable GSK3203591 + GSK3368715 Preclinical - Cell culture Actionable In a preclinical study, GSK3203591 and GSK3368715 worked synergistically to inhibit viability of diffuse large B-cell lymphoma cell lines in culture (PMID: 31257072). 31257072
Unknown unknown acute myeloid leukemia not applicable GSK3368715 Preclinical - Cell culture Actionable In a preclinical study, GSK3368715 inhibited growth of acute myeloid leukemia cell lines in culture, and demonstrated cytotoxicity in 50% of cell lines tested (PMID: 31257072). 31257072
Unknown unknown pancreatic adenocarcinoma not applicable GSK3368715 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK3368715 inhibited growth of a pancreatic adenocarcinoma cell line in culture, and inhibited tumor growth in xenograft models (PMID: 31257072). 31257072