Potential Treatment Combinations for Melanoma Identified Through Novel Screening Approach

David F. Stern, PhD

A new drug screening method revealed that cholesterol-reducing statin drugs used in combination with cyclin-dependent kinase inhibitors might serve as an effective treatment approach for certain types of melanoma exhibiting mutations of NRAS and KRAS, according to the results of research published in Cancer Discovery.

Some targeted therapies, including ipilimumab and vemurafenib, have been developed for patients with melanoma, with others such as dabrafenib and trametinib currently in clinical trials. However, not all patients with the specific mutations targeted respond to these drugs, and those who do respond eventually become resistant to the drugs and relapse.

David F. Stern, PhD, professor of Pathology and associate director of Shared Resources at the Yale Cancer Center, and colleagues used combinational drug screening to identify effective drug combinations for patients with BRAF-mutated melanomas, including cases resistant to vemurafenib, and RAS-mutated melanomas resistant to several therapies. The intent was to determine whether certain combinations could overcome drug resistance and serve as an effective treatment for cancers driven by signaling molecules like RAS that currently cannot be targeted.

The researchers developed an in vitro, high-throughput screen that tested the effectiveness of drugs as single agents or in pairs against cell lines with mutations of RAS, mutations of BRAF, and lines without mutations in either of those genes. A total of 150 drugs were evaluated for effectiveness as single agents. Those drugs were narrowed down to 40 drugs that were tested for their efficacy in combinations.

According to the study, different cell lines were sensitive to different combinations of drugs identified through the screen. Certain combinations effective against BRAF-driven melanoma cell lines were also effective against BRAF-driven lines that were resistant to single-agent therapy. The researchers found that statins were able to kill certain RAS-driven cell lines.

“These agents may be extremely useful as partner agents in combination therapy,” Stern said. “Since multiple cyclin-dependent kinase inhibitors are already in human clinical trials, there may be a short path to testing the combination of a statin plus a cyclin-dependent kinase inhibitor in patients with RAS-driven melanoma. There is a great need for drugs to treat cancers driven by RAS. RAS proteins are inappropriately active in up to a third of all human cancers, including melanoma, lung, and pancreatic cancers.”

Stern noted that one combination that showed efficacy in vitro—the statin drug simvastatin and the kinase inhibitor flavopiridol—also worked in vivo by significantly reducing the growth of a RAS-driven human melanoma cell line that had been transplanted into mice.

Held MA, Langdon CG, Platt JT, et al. Genotype-selective combination therapies for melanoma identified by high-throughput drug screening. Cancer Discov. 2013;3(1):52-67.