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Updated: Nov 24, 2025

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Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies

Ozgecan Dulgar1, Tugce Kutuk1, Zeynep Eroglu2,3

  • 1Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.

American Journal of Clinical Dermatology
|December 28, 2020
PubMed

Insights

BRAF-mutated melanomas respond to targeted therapies, but resistance limits durability. Research explores strategies like combination therapies and immunotherapy to overcome resistance and improve long-term survival for advanced melanoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Activating BRAF oncogene mutations are present in approximately 50% of cutaneous melanomas.
  • BRAF and downstream MEK inhibition targets this vulnerability in advanced melanoma with BRAFV600 mutations.
  • Approved drug combinations offer treatment options for BRAF-mutated advanced melanomas.

Purpose of the Study:

  • To review the efficacy and limitations of BRAF/MEK inhibitors in advanced melanoma.
  • To explore known mechanisms of resistance to BRAF/MEK inhibition.
  • To discuss strategies for overcoming treatment resistance and improving long-term outcomes.

Main Methods:

  • Review of clinical trial data, including five-year survival benefits.
  • Analysis of documented mechanisms of resistance to BRAF/MEK inhibitors.
  • Examination of therapeutic strategies to overcome resistance.

Main Results:

  • BRAF/MEK inhibitors induce rapid responses, but durability is often limited.
  • Long-term survival benefit is observed in approximately one-third of patients at five years.
  • Multiple resistance mechanisms exist, including MAPK reactivation and non-genetic alterations.

Conclusions:

  • Despite initial efficacy, resistance to BRAF/MEK inhibitors is a significant challenge in advanced melanoma.
  • Strategies such as altered dosing, combination kinase inhibitors, and immunotherapy are being investigated to enhance durability.
  • Overcoming resistance is crucial for improving long-term survival in patients with BRAF-mutated melanomas.

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