Using drug combinatorial screening can identify effective combinations for melanomas with genetic variants, including BRAF and RAS mutations that confer either primary or secondary resistance to known therapies. According to a study published in the January issue of Cancer Discovery, the high-throughput drug screening method identified previously unrecognized patterns of drug interaction with the potential for clinical efficacy in treating defined subgroups of melanoma. Such a screening approach may be applicable to other cancers. Using an array of small-molecule inhibitors on early-passage melanoma cultures, the researchers applied a systematic combinatorial high-throughput drug screening (cHTS) approach to evaluate the selectivity of drugs, alone and in pairs, and in the context of BRAF- or RAS-activating mutations (affecting 40 percent and 20 percent of human melanomas, respectively) in the hopes that more defined genotype-selective patterns would yield higher efficacies, thus combatting the problem of limited responses to single agents. “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,” says co-author David Stern, Ph.D., from Yale University School of Medicine in New Haven, Conn. “There is a great need for drugs to […]
Using drug combinatorial screening can identify effective combinations for melanomas with genetic variants, including BRAF and RAS mutations that confer either primary or secondary resistance to known therapies. According to a study published in the January issue of Cancer Discovery, the high-throughput drug screening method identified previously unrecognized patterns of drug interaction with the potential for clinical efficacy in treating defined subgroups of melanoma. Such a screening approach may be applicable to other cancers.
Using an array of small-molecule inhibitors on early-passage melanoma cultures, the researchers applied a systematic combinatorial high-throughput drug screening (cHTS) approach to evaluate the selectivity of drugs, alone and in pairs, and in the context of BRAF- or RAS-activating mutations (affecting 40 percent and 20 percent of human melanomas, respectively) in the hopes that more defined genotype-selective patterns would yield higher efficacies, thus combatting the problem of limited responses to single agents.
“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,” says co-author David Stern, Ph.D., from Yale University School of Medicine in New Haven, Conn. “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.”
Single agent analyses of 150 drugs were individually conducted and then cHTS tests were performed on 40 combinations. Genotype-selective combinations were determined using data for drug pairings that yielded an average minimum of 15 percent growth inhibition exclusively in a genotypic group. The researchers found melanoma cell lines driven by BRAF and RAS were sensitive to different novel combinations of drugs including the pairing of statins with cyclin-dependent kinase inhibitors.
“Our high-throughput screening approach is applicable to other types of cancer, including lung and pancreatic cancer,” Stern says. “A major challenge is in picking the appropriate agents for combination screening, since with multiple doses per agent, the scale of a screen needed for all combinations grows rapidly. This requires careful evaluation of single agents and analytical methods for choosing the best candidates for follow-up in combinations.”
