Combinatorial Drug Screening Points to Statins as Potential Antimelanoma Agents

Cancer researchers have used a novel combinatorial high-throughput drug screening technique to identify potential drug combinations capable of killing melanoma tumors resistant to known chemotherapeutic agents.

Investigators at Yale University (New Haven, CT, USA) used this methodology to evaluate the effectiveness of anticancer drugs, alone and in pairs, against three varieties of melanoma cell lines. One line, which represents approximately 20% of human melanomas, is driven by mutations in the RAS gene. The second line, which accounts for about 40%–50% of melanomas, is driven by mutations in the BRAF gene. The third cell line comprised melanomas without mutations in either the RAS or BRAF genes.

Initially the investigators screened 150 drugs as single agents. Forty drug combinations were then tested against the three melanoma cell lines. Results published in the December 13, 2012, online edition of the journal Cancer Discovery revealed several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to the drug vemurafenib.

Drugs that inhibited both the EGF (epidermal growth factor) receptor and AKT (protein kinase B) sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo.

“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 senior author Dr. David F. Stern, professor of pathology at Yale University. “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.”

“These agents may be extremely useful as partner agents in combination therapy,” said Dr. Stern. “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 and lung and pancreatic cancers.”

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