Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib).

Autor:	Germann UA; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Furey BF; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Markland W; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Hoover RR; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Aronov AM; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Roix JJ; BioMed Valley Discoveries, Inc., Kansas City, Missouri., Hale M; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Boucher DM; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Sorrell DA; Horizon Discovery Ltd, Cambridge, United Kingdom., Martinez-Botella G; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Fitzgibbon M; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Shapiro P; University of Maryland School of Pharmacy, Baltimore, Maryland., Wick MJ; START, San Antonio, Texas., Samadani R; University of Maryland School of Pharmacy, Baltimore, Maryland., Meshaw K; Charles River Discovery Services, Morrisville, North Carolina., Groover A; BioMed Valley Discoveries, Inc., Kansas City, Missouri., DeCrescenzo G; BioMed Valley Discoveries, Inc., Kansas City, Missouri., Namchuk M; Vertex Pharmaceuticals Inc, Cambridge, Massachusetts., Emery CM; BioMed Valley Discoveries, Inc., Kansas City, Missouri., Saha S; BioMed Valley Discoveries, Inc., Kansas City, Missouri., Welsch DJ; BioMed Valley Discoveries, Inc., Kansas City, Missouri. dwelsch@biomed-valley.com.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2017 Nov; Vol. 16 (11), pp. 2351-2363. Date of Electronic Publication: 2017 Sep 22.
DOI:	10.1158/1535-7163.MCT-17-0456
Abstrakt:	Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway (NCT01781429, NCT02296242, and NCT02608229). Mol Cancer Ther; 16(11); 2351-63. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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