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Updated: Mar 8, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
MAPK pathway in melanoma part II-secondary and adaptive resistance mechanisms to BRAF inhibition
Teresa Amaral1, Tobias Sinnberg2, Friedegund Meier3
1Center for Dermatooncology, Department of Dermatology, Liebermeisterstr. 25, University Hospital Tübingen, 72076 Tübingen, Germany; Portuguese Air Force Health Direction, Paço do Lumiar, 1649-020 Lisbon, Portugal.
Abstract:
BRAF mutation can be identified in about 45% of the patients with metastatic melanoma. In these patients, BRAF and MEK inhibitors are able to induce rapid responses and to prolong survival. However, a significant percentage of patients will develop resistance to targeted therapy and will have progressive disease. MAPK pathway is the most important pathway involved in BRAF/MEK inhibition resistance, particularly MAPK pathway reactivation. Resistance mechanisms can be classified as 1) primary or intrinsic characterised by no response to therapy, 2) secondary or acquired with MAPK pathway reactivation after a time of tumour regression and 3) as adaptive with initial response and early resistance. BRAF inhibition also alters the immune response. Several publications have described immune effects of BRAF inhibition in melanoma tumours, showing that combining targeted and immunotherapy can improve response, despite a possible cross-resistance. Here, we continue the review on resistance mechanisms to BRAF/MEK inhibition and focus on the secondary and adaptive mechanisms.
Insights
Targeted therapy for BRAF-mutated melanoma shows promise but resistance develops. This review focuses on secondary and adaptive resistance mechanisms, particularly MAPK pathway reactivation, impacting treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- BRAF mutations are common in metastatic melanoma, driving targeted therapy use.
- BRAF and MEK inhibitors offer survival benefits but acquired resistance limits long-term efficacy.
- Mechanisms of resistance, including MAPK pathway reactivation, are crucial for understanding treatment failure.
Purpose of the Study:
- To review secondary and adaptive resistance mechanisms to BRAF/MEK inhibitors in melanoma.
- To explore the role of MAPK pathway reactivation in acquired resistance.
- To discuss the interplay between targeted therapy and immune response in melanoma.
Main Methods:
- Literature review of resistance mechanisms to BRAF/MEK inhibitors.
- Analysis of studies on MAPK pathway reactivation.
- Examination of research on immune effects of BRAF inhibition.
Main Results:
- Resistance to BRAF/MEK inhibitors is often due to MAPK pathway reactivation.
- Secondary resistance involves acquired resistance with pathway reactivation after initial response.
- Adaptive resistance presents as early resistance after initial tumor regression.
Conclusions:
- Understanding secondary and adaptive resistance is key to overcoming treatment failure in BRAF-mutated melanoma.
- Targeted therapy impacts the immune microenvironment, suggesting combination strategies.
- Further research into resistance mechanisms may reveal novel therapeutic targets.
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