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Updated: Feb 12, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

Ileabett M Echevarría-Vargas1, Patricia I Reyes-Uribe1, Adam N Guterres1

  • 1Molecular & Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.

EMBO Molecular Medicine
|April 14, 2018
PubMed

Insights

Drug resistance in NRAS-mutant melanoma can be overcome by combining BET and MEK inhibitors. This synergistic approach curbs tumor growth and improves survival in resistant melanoma models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Drug resistance is a major challenge in melanoma treatment, particularly for NRAS-mutant cases.
  • BET proteins, including BRD4, are overexpressed in NRAS-mutant melanoma and linked to poor patient outcomes.

Purpose of the Study:

  • To investigate novel therapeutic strategies for NRAS-mutant melanoma.
  • To evaluate the efficacy of combining BET and MEK inhibitors in overcoming drug resistance.

Main Methods:

  • Utilized NRAS-mutant melanoma models to test drug combinations.
  • Assessed tumor growth and survival in mice.
  • Performed transcriptomic and proteomic analyses.

Main Results:

  • Co-targeting BET and MEK inhibitors synergistically inhibited NRAS-mutant melanoma growth.
  • This combination prolonged survival in mice with tumors resistant to MAPK inhibitors and immunotherapy.
  • The treatment mitigated resistance signatures, downregulated TCF19, and induced apoptosis.

Conclusions:

  • Combining MEK and BET inhibitors offers a potent strategy to overcome therapeutic resistance in NRAS-mutant melanoma.
  • This approach presents a potential salvage therapy for treatment-resistant melanomas and possibly other cancers.
Keywords:
BETcombination therapydrug resistancemelanomamutant NRAS

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