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Updated: Apr 29, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Adaptive resistance to RAF inhibitors in melanoma
Curtis H Kugel1, Andrew E Aplin
1Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Jefferson College of Graduate Studies, Thomas Jefferson University, Philadelphia, PA, USA.
Abstract:
The discovery of activating mutations in BRAF at high frequency in cutaneous melanoma opened the door to new treatment options, which have resulted in significantly better patient outcomes. Treatments such as the FDA-approved RAF inhibitor vemurafenib and the more recently approved dabrafenib and trametinib combination therapy are designed to target the ERK1/2 pathway. Initial success in targeting this pathway is evidenced by the high percentage of melanoma patients who undergo tumor remission. However, the beneficial effects of these targeted therapies are usually short-lived due to the development of resistance, which leads to disease progression. As a result, studies have focused on the acquired forms of resistance that develop following continued exposure to therapy. Conversely, far fewer studies have investigated the adaptive forms of resistance, which activate rapidly, promote cell survival, and may underlie the development of acquired resistance by providing melanoma cells the time to develop additional mutations. We provide a detailed review of the known mechanisms of adaptive resistance in melanoma and relate them to similar responses to targeted therapies in other tumor types.
Insights
Targeted melanoma therapies show initial success but resistance limits outcomes. This review details adaptive resistance mechanisms, crucial for understanding and overcoming treatment failure in BRAF-mutant melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Activating BRAF mutations are common in cutaneous melanoma, leading to targeted therapies like RAF inhibitors.
- Targeted therapies (e.g., vemurafenib, dabrafenib/trametinib) initially improve patient outcomes by targeting the ERK1/2 pathway.
- Therapeutic resistance, particularly acquired resistance, limits the long-term efficacy of these treatments.
Purpose of the Study:
- To review known mechanisms of adaptive resistance in melanoma.
- To explore the role of adaptive resistance in the development of acquired resistance.
- To compare adaptive resistance mechanisms in melanoma to those in other cancer types.
Main Methods:
- Literature review of studies on melanoma resistance to targeted therapies.
- Analysis of mechanisms underlying adaptive and acquired resistance.
- Comparative analysis of resistance pathways across different tumor types.
Main Results:
- Adaptive resistance mechanisms activate rapidly, promoting melanoma cell survival.
- Adaptive resistance may provide a window for melanoma cells to acquire mutations leading to acquired resistance.
- Similar adaptive resistance responses are observed in other cancers treated with targeted therapies.
Conclusions:
- Understanding adaptive resistance is critical for developing strategies to overcome treatment failure in melanoma.
- Targeting adaptive resistance mechanisms may enhance the durability of response to BRAF-targeted therapies.
- Insights from melanoma can inform resistance research in other malignancies.
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