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|Ref Type||Journal Article|
|Authors||Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ|
|Title||Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib).|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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 BRAFV600E-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.|
|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|
|Ulixertinib||BVD-523||ERK Inhibitor (pan) 15||Ulixertinib (BVD-523) inhibits both ERK 1 and 2, thereby preventing the activation of ERK-mediated signal transduction pathways and resulting in growth inhibition (PMID: 28939558).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|HRAS||F82L||missense||unknown||HRAS F82L does not lie within any known functional domains of the Hras protein (UniProt.org). F82L has been identified in the scientific literature (PMID: 28939558, PMID: 25360634), but has not been biochemically characterized and therefore, its effect on Hras protein function is unknown (PubMed, Apr 2020).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600E||colorectal cancer||sensitive||Ulixertinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Ulixertinib (BVD-523) inhibited Erk signaling in colorectal cancer cells harboring BRAF V600E, resulted in cell cycle arrest in culture and tumor growth inhibition in cell line xenograft models (PMID: 28939558).||28939558|
|BRAF V600E||melanoma||sensitive||Ulixertinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Ulixertinib (BVD-523) inhibited Erk signaling in melanoma cells harboring BRAF V600E, resulted in cell cycle arrest in culture and tumor growth inhibition in cell line xenograft models (PMID: 28939558).||28939558|