Reference Detail

Ref Type

Journal Article

PMID

(28939558)

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	11	2017 Nov	2351-2363	Mol Cancer Ther

URL

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.

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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
Ulixertinib		BVD-523\|BVD 523\|BVD523	ERK Inhibitor (pan) 21	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, Jun 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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