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Mol Carcinog. 2019 Jun 12. doi: 10.1002/mc.23047. [Epub ahead of print]

Targeting ERK beyond the boundaries of the kinase active site in melanoma.

Author information

1
Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas.
2
Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
3
Department of Chemistry and Biochemistry, The City College of New York, New York, New York.
4
Departments of Anatomic Pathology and Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
5
Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, Texas.

Abstract

Extracellular signal-regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF-V600E mutant melanoma, ERK inhibition has emerged as a viable clinical approach to abrogate signaling through the ERK pathway, even in cases where MEK and Raf inhibitor treatments fail to induce tumor regression due to resistance mechanisms. Several ERK inhibitors that target the active site of ERK have reached clinical trials, however, many critical ERK interactions occur at other potentially druggable sites on the protein. Here we discuss the role of ERK signaling in cell fate, in driving melanoma, and in resistance mechanisms to current BRAF-V600E melanoma treatments. We explore targeting ERK via a distinct site of protein-protein interaction, known as the D-recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF-V600E melanoma. Targeting the DRS with inhibitors in melanoma has the potential to not only disrupt the catalytic apparatus of ERK but also its noncatalytic functions, which have significant impacts on spatiotemporal signaling dynamics and cell fate.

KEYWORDS:

D-recruitment site; docking site; protein-protein interaction

PMID:
31190430
DOI:
10.1002/mc.23047

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