Researchers may have uncovered a novel epigenetic pathway involved in the development of treatment resistance in melanoma and a chemical reagent that may be effective in resensitizing treatment-resistant tumors to targeted therapies, according to a recent study published by Wu et al in The Journal of Clinical Investigation.
Background
Understanding the molecular basis for therapeutic resistance as a major contributor to a lack of long-term treatment success is one of the chief concerns in cancer research and clinical care. In patients with melanoma, the main targeted therapeutic strategy is directed against the mitogen-activated protein kinase (MAPK) pathway. However, the vast majority of patients experience resistance to MAPK inhibitor therapies within 1 year.
“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. We are excited about the broader implications this study has for the potential treatment of patients with acquired resistance to cancer therapies,” highlighted co–senior study author Rhoda Alani, MD, the Herbert Mescon Chair of Dermatology at the Boston University Chobanian & Avedisian School of Medicine and Chief of Dermatology at the Boston Medical Center
Study Methods and Results
In the recent study, the researchers used both cancer cell lines grown in the laboratory and human melanoma tumors grown in experimental models to evaluate the epigenetic influences associated with melanoma progression and their response to targeted therapies.
The researchers determined that a critical resistance mechanism for melanoma involved the epigenetic mediator CoREST. They found that this treatment resistance could be targeted by corin, a recently designed dual-functioning small molecule inhibitor of CoREST. The researchers provided the molecular rationale for how CoREST complex targeting may be harnessed for an important therapeutic goal in a broad range of epigenetic contexts, including melanoma.
Conclusions
The researchers indicated that the clinical implications of their findings may be significant—suggesting that similar epigenetic events may be associated with treatment resistance in other types of cancers. They hope their research can influence the development of novel high-specificity epigenetic inhibitors like corin that allow for the resensitization of these tumors to effective targeted therapies as well as disease remission with minimal side effects.
“We also expect that these studies will result in the improved efficacy of anticancer targeted drugs while limiting the development of drug resistance in cancers through the combined use of targeted epigenetic therapies,” concluded Dr. Alani.
Disclosure: The research in this study was supported in part by a Karin Grunebaum Cancer Foundation Research Award, a grant from the National Institutes of Health, and a Melanoma Research Alliance Established Investigator Award. For full disclosures of the study authors, visit jci.org.
