The ERK5 pathway in BRAFV600E melanoma cells plays a role in development of acquired resistance to dabrafenib but not vemurafenib

FEBS Lett. 2024 Aug;598(16):2011-2027. doi: 10.1002/1873-3468.14960. Epub 2024 Jul 8.

Abstract

Malignant melanoma, an aggressive skin cancer with a poor prognosis, frequently features BRAFV600E mutation resulting in activation of the MAPK pathway and melanocyte proliferation and survival. BRAFV600E inhibitors like vemurafenib and dabrafenib have enhanced patient survival, yet drug resistance remains a significant challenge. We investigated the role of the ERK5 pathway in BRAFV600E melanoma cells and cells with acquired resistance to PLX4720 (vemurafenib) and dabrafenib. In BRAFV600E melanoma, ERK5 inhibition minimally affected viability compared to ERK1/2 inhibition. In vemurafenib-resistant cells, ERK5 inhibition alone didn't impact viability or restore drug sensitivity to vemurafenib. However, in dabrafenib-resistant cells, ERK5 inhibition reduced viability and enhanced the anti-proliferative effect of MEK1/2 inhibition. Targeting the ERK5 pathway may represent a therapeutic opportunity in dabrafenib-resistant melanoma.

Keywords: BRAF; ERK5; dabrafenib; drug‐resistance; melanoma; vemurafenib.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Humans
  • Imidazoles* / pharmacology
  • Indoles / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • Melanoma* / metabolism
  • Melanoma* / pathology
  • Mitogen-Activated Protein Kinase 7* / genetics
  • Mitogen-Activated Protein Kinase 7* / metabolism
  • Mutation
  • Oximes* / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf* / genetics
  • Proto-Oncogene Proteins B-raf* / metabolism
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Sulfonamides / pharmacology
  • Vemurafenib* / pharmacology

Substances

  • Oximes
  • dabrafenib
  • Proto-Oncogene Proteins B-raf
  • Imidazoles
  • Vemurafenib
  • BRAF protein, human
  • Mitogen-Activated Protein Kinase 7
  • Indoles
  • Sulfonamides
  • MAPK7 protein, human
  • Protein Kinase Inhibitors