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

Abstract

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.

• Authors: Ursula A Germann, Brinley F Furey, William Markland, Russell R Hoover, Alex M Aronov, Jeffrey J Roix, Michael Hale, Diane M Boucher, David A Sorrell, Gabriel Martinez-Botella, Matthew Fitzgibbon, Paul Shapiro, Michael J Wick, Ramin Samadani, Kathryn Meshaw, Anna Groover, Gary DeCrescenzo, Mark Namchuk, Caroline M Emery, Saurabh Saha, Dean J Welsch
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 16 Issue 11 Pg. 2351-2363 (11 2017) ISSN: 1538-8514 [Electronic] United States
• PMID: 28939558 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Aminopyridines
• Protein Kinase Inhibitors
• Pyrroles
• ulixertinib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Aminopyridines (administration & dosage)
• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Humans
• MAP Kinase Signaling System (drug effects)
• Melanoma (drug therapy, genetics, pathology)
• Mice
• Mutation
• Protein Kinase Inhibitors (administration & dosage)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Pyrroles (administration & dosage)
• Xenograft Model Antitumor Assays