A Step Toward Overcoming a Melanoma Drug Resistance Pathway

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A study conducted at the Boston University Chobanian & Avedisian School of Medicine investigating BRAF-mutant melanomas that develop resistance to mitogen-activated protein kinase (MAPK) inhibitors identified a critical pathway in the resistance phenomenon, as well as a chemical reagent that can resensitize therapy-resistant cancers to targeted therapies, according to the university.¹

The study appeared online today in the Journal of Clinical Investigation.

The study authors found that the CoREST repressor complex is a critical mediator of the major distinct melanoma phenotypes, and that corin treatment of melanoma cells leads to phenotype reprogramming. Corin is a recently developed potent and specific bivalent small molecule inhibitor of the CoREST complex.² 

Boston University reports that the researchers used both “cancer cell lines grown in the lab and human melanoma tumors grown in experimental models.” This involved treating a panel of phenotypically distinct melanoma cell lines with the CoREST inhibitor corin for 24 hours. Corin treatment was found to inhibit melanoma growth in BRAF-inhibitor resistant melanomas and to resensitize them to BRAF-inhibitor therapy.

Previous research by this group demonstrated strong growth inhibition by corin in all melanoma and leukemia cell lines they tested, in addition to 50% of the breast cancer cell lines and 70% of the colon cancer cell lines.³ 

The findings suggest that CoREST inhibitors may prove beneficial to patients with BRAF-resistant melanoma, the study authors wrote.

“Although the cancer research community has been very successful in developing specific targeted therapies for the genetic events driving many cancers, most patients are unable to be cured of their cancers due to acquired resistance mechanisms,” said co-corresponding author Rhoda Alani, MD, the Herbert Mescon Chair of Dermatology at Boston University Chobanian & Avedisian School of Medicine, in a news release.¹ 

“We are excited about the broader implications this study has for the potential treatment of patients with acquired resistance to cancer therapies mediated by epigenetic events.”

More on BRAF-Mutant Melanoma 

Progression-Free Survival of BRAF-Mutant Melanoma Improved by Combination Therapy 

Combos Lead Excitement in BRAF+ Melanoma, but More Pain Points are Ready to be Tackled 

References 

1. Boston University School of Medicine. Researchers identify critical pathway responsible for melanoma drug resistance. News release. February 1, 2024. https://www.eurekalert.org/news-releases/1033127
2. Wu M, Hanly A, Gibson F, et al. The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma. J Clin Invest. 2024. https://doi.org/10.1172/JCI171063.
3. Kalin JH, et al. Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nat Commun. 2018;9(1):53.