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

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 dev...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2017-11, Vol.16 (11), p.2351-2363
Main Authors: Germann, Ursula A, Furey, Brinley F, Markland, William, Hoover, Russell R, Aronov, Alex M, Roix, Jeffrey J, Hale, Michael, Boucher, Diane M, Sorrell, David A, Martinez-Botella, Gabriel, Fitzgibbon, Matthew, Shapiro, Paul, Wick, Michael J, Samadani, Ramin, Meshaw, Kathryn, Groover, Anna, DeCrescenzo, Gary, Namchuk, Mark, Emery, Caroline M, Saha, Saurabh, Welsch, Dean J
Format: Article
Language:English
Subjects:
Aberration
Activation
Aminopyridines - administration & dosage
Animals
Anticancer properties
Antitumor activity
Cancer
Caspase
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Clinical trials
Disease resistance
Drug Resistance, Neoplasm - genetics
Extracellular signal-regulated kinase
Growth inhibition
Humans
In vivo methods and tests
Inhibitors
Kinases
MAP kinase
MAP Kinase Signaling System - drug effects
Medical research
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Melanoma - pathology
Mice
Mutation
Phosphorylation
Protein Kinase Inhibitors - administration & dosage
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - genetics
Pyrroles - administration & dosage
Raf protein
Signal transduction
Signaling
Substrate inhibition
Substrates
Therapy
Tumors
Xenograft Model Antitumor Assays
Xenografts
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Summary: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. 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 xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in and 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). .
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-17-0456