Yale team identifies successful combination drug therapies for melanoma mutations

Yale Cancer Center researchers have identified several effective combinations of therapies that inhibit melanomas driven by two of the most formidable cancer genes. Some combinations include cholesterol-lowering statin drugs. The study appears in the journal Cancer Discovery.

The Yale scientists were seeking to overcome the problems of resistance and partial response to single-drug cancer therapy in patients with melanoma. Until now there has been no effective method reported to target mutated RAS melanoma oncogenes through combination drug therapy. RAS genes drive many types of cancer that are notoriously difficult to treat. T

he BRAF gene is a second key driver of melanoma and can be targeted by new therapies. However, even when single-drug therapy is initially successful, recurrence nearly always occurs and is associated with poor patient prognosis.

Using novel high-throughput screening techniques, the Yale researchers mixed and matched among 150 small molecule compounds, searching for pairs that could inhibit melanoma cell growth. They used cell lines derived directly from human metastasized melanomas. The compounds were all genotype-selective for RAS or BRAF mutations.

The team identified several unique combinations, including some that inhibited cells with resistance to vemurafenib, the BRAF inhibitor drug used in the treatment of late-state melanoma. Further, they discovered that combining statins with drugs that inhibited cyclin-dependent protein kinase enzymes, which regulate and promote the cellular growth of cancer, produced a similar response with both RAS- and BRAF-mutated oncogenes.

This study is believed to be the first to show extensive positive results of combination drug therapy, including combinations that include statins, in fighting late-stage melanoma, and could set the stage for clinical trials in patients.