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The role of mitogen-activated protein targeting in melanoma beyond BRAFV600
1Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
Purpose Of Review:
Targeted therapy in melanoma is well established for patients with tumors harboring BRAF mutations, but less so for other molecularly defined subsets. In this review, emerging preclinical, genomic, and early clinical data are discussed regarding the use of mitogen-activated protein (MAPK) pathway inhibitors in other molecular subsets of melanoma.
Recent Findings:
There are now four well defined subsets of melanoma based on The Cancer Genome Atlas: BRAF driven, NRAS driven, NF1 mutant, and 'triple wild type'. The former three subtypes predict signaling through the MAPK pathway and sensitivity to inhibitors of this pathway's mediators. With ongoing translation of preclinical findings into clinical trials, there is great hope that these strategies will improve the care of patients who fall into these other molecular subsets.
Summary:
A more comprehensive understanding of genetically defined subtypes of melanoma is emerging. Efforts in the clinic are already underway, but additional, well designed trials of MAPK-targeted therapy planned and needed.
Insights
Targeted therapy for melanoma is expanding beyond BRAF mutations to other molecular subtypes. Research shows promise for mitogen-activated protein (MAPK) pathway inhibitors in NRAS, NF1, and triple wild-type melanoma.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Targeted therapy for melanoma is primarily established for BRAF-mutated tumors.
- Limited therapeutic options exist for other molecularly defined melanoma subsets.
- Melanoma classification has advanced, identifying distinct genetic subtypes.
Purpose of the Study:
- To review emerging preclinical, genomic, and early clinical data on mitogen-activated protein (MAPK) pathway inhibitors.
- To explore the application of MAPK pathway inhibitors in non-BRAF mutated melanoma subsets.
- To discuss the potential of targeted therapies for diverse melanoma molecular profiles.
Main Methods:
- Review of preclinical findings.
- Analysis of genomic data.
- Evaluation of early-phase clinical trial results.
Main Results:
- Four major melanoma subsets are defined: BRAF-driven, NRAS-driven, NF1-mutant, and 'triple wild type'.
- NRAS-driven, NF1-mutant, and triple wild-type melanomas exhibit MAPK pathway signaling.
- These subtypes show potential sensitivity to MAPK pathway inhibitors.
- Ongoing clinical trials are translating preclinical findings into patient care.
Conclusions:
- A deeper understanding of genetically defined melanoma subtypes is developing.
- Clinical efforts are underway to test MAPK-targeted therapies in these subsets.
- Well-designed clinical trials are crucial for advancing MAPK-targeted therapy in melanoma.
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