An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential
Liqin Wang1, Rodrigo Leite de Oliveira1, Sanne Huijberts2
1Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
Abstract:
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
Insights
Drug-resistant melanomas develop vulnerabilities to reactive oxygen species (ROS). Treatment with vorinostat selectively targets these resistant cells, offering a new therapeutic strategy for BRAF+MEK inhibitor-resistant melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- BRAF(V600E) mutant melanomas often develop resistance to BRAF and MEK kinase inhibitors.
- This resistance is frequently linked to the reactivation of the mitogen-activated protein kinase (MAPK) pathway.
Purpose of the Study:
- To identify novel therapeutic strategies for MAPK inhibitor-resistant melanomas.
- To investigate acquired vulnerabilities in drug-resistant melanoma cells.
Main Methods:
- Assessing reactive oxygen species (ROS) levels in resistant melanoma cells.
- Utilizing the histone deacetylase inhibitor vorinostat to target SLC7A11 expression.
- Evaluating tumor regression in mouse models and clinical studies of advanced melanoma.
Main Results:
- Melanoma resistance to BRAF+MEK inhibitors correlates with increased ROS levels.
- Vorinostat treatment reduces SLC7A11, causing lethal ROS accumulation in resistant cells.
- Selective apoptosis of drug-resistant melanoma cells and significant tumor regression observed in preclinical and clinical settings.
Conclusions:
- Targeting elevated ROS levels presents a promising therapeutic approach for BRAF+MEK inhibitor-resistant melanoma.
- Vorinostat demonstrates selective tumor cell ablation, providing clinical proof of concept for this novel therapy.
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