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Updated: May 7, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma

Jessie Villanueva1, Jeffrey R Infante, Clemens Krepler

  • 1Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.

Cell Reports
|September 24, 2013
PubMed

Insights

Melanoma patients can develop resistance to BRAF and MEK inhibitors through new mutations like MEK2-Q60P and BRAF amplification. A triple therapy combining BRAF, MEK, and PI3K/mTOR inhibitors shows promise in overcoming this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRAF and MEK inhibitors offer clinical benefits for melanoma patients.
  • Acquired resistance to these targeted therapies is a significant clinical challenge.

Purpose of the Study:

  • To investigate the genetic mechanisms underlying resistance to BRAF and MEK inhibitors in melanoma.
  • To identify novel therapeutic strategies to overcome treatment resistance.

Main Methods:

  • Analysis of melanoma patient samples and xenograft tumors.
  • Genomic analysis to identify mutations and amplifications.
  • Cellular studies involving chronic drug exposure.
  • Assessment of MAPK signaling pathway activation.
  • In vivo efficacy studies of combination therapies.

Main Results:

  • A novel MEK2-Q60P mutation and BRAF gain/amplification were identified in resistant melanoma.
  • Melanoma cells acquired MEK2-Q60P mutation and BRAF amplification upon chronic MEK inhibitor exposure.
  • These genetic events conferred resistance to both BRAF and MEK inhibitors by sustaining MAPK signaling.
  • A triple combination therapy (dabrafenib, trametinib, GSK2126458) demonstrated sustained tumor growth inhibition.

Conclusions:

  • Concurrent genetic events sustaining MAPK signaling drive resistance to BRAF and MEK inhibitors in melanoma.
  • Targeting MEK2 mutations and BRAF amplification is crucial for overcoming resistance.
  • Combination therapies involving PI3K/mTOR inhibition represent a promising strategy for resistant melanoma.

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