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Potential Drug Combinations Identified for Treatment of Melanoma

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Certain drug combinations were effective against cell lines resistant to single agents

Researchers using a new method to identify potential anticancer drug combinations revealed that pairing statins with cyclin-dependent kinase inhibitors could be a potentially effective approach to treating intractable melanomas driven by mutations in the NRAS and KRAS genes.

“The identification of gene mutations that drive specific subsets of cancers has had a major beneficial impact on treatments for these patients. But, such mutations can only be identified for some cancers. Some patients who have a specific cancer-driving genetic mutation never respond to the matching drug, while nearly all those who initially respond eventually become resistant to the effects of the drug and their cancers relapse,” said David F. Stern, PhD, professor of pathology at Yale University School of Medicine in New Haven, Connecticut.

On this basis, Stern and colleagues reasoned that treating patients with drug combinations might be the key to addressing the problem of drug resistance. Drug combinations may also allow for effective treatment of those cancers driven by signaling molecules that cannot be targeted, such as RAS.

For their study, the researchers focused on 3 types of melanoma cell lines: those driven by mutations in the RAS gene (representing approximately 20% of human melanomas), those driven by mutations in the BRAF gene (40%-50% of melanomas), and those without mutations in either the RAS or BRAF genes. Stern and colleagues developed an in vitro, high-throughput screen to test the effectiveness of anticancer drugs, alone and in pairs, against these cell lines.

After analyzing 150 drugs as single agents, the researchers narrowed the anticancer drugs down to 40 for combination testing. Study results, published in Cancer Discovery, showed that melanoma cell lines driven by BRAF and RAS were sensitive to different combinations of drugs. Some combinations that killed BRAF-driven melanoma cell lines were also effective against BRAF-driven melanoma cell lines already resistant to a single agent. Preventing or managing drug resistance may be possible with these combinations.

“Perhaps the most interesting observation was that several drug combinations that included a statin, a drug class used clinically to lower cholesterol, killed RAS-driven melanoma cell lines, given the lack of success in treating such cancers,” said Stern.

Stern continued, “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 and lung and pancreatic cancers.”

Source: AACR.