Drug Combinations Target Mutant BRAF Melanomas
Melanomas with RAS mutation sensitive to statin, cyclin-dependent kinase inhibitor combo
FRIDAY, Dec. 14 (HealthDay News) -- Melanomas carrying mutations that make them resistant to many drugs can be effectively targeted by drug combinations, some of which include statins, according to a study published online Dec. 13 in Cancer Discovery.
Matthew A. Held, Ph.D., from the Yale University School of Medicine in New Haven, Conn., and colleagues tested the efficacy of pairwise combinations of 40 small molecule compounds (of 150 tested as single agents) on melanoma cells containing activating mutations in the RAS gene, the BRAF gene (including melanomas resistant to vemurafenib, which targets BRAF mutations), or neither gene.
The researchers identified several effective inhibitor combinations. Melanomas with RAS mutations were generally more resistant to combination treatment than melanomas with BRAF mutations. However, in vitro and in vivo, they were sensitive to combinations of statins and cyclin-dependent kinase inhibitors. Simvastatin plus flavopiridol were also effective in reducing the growth of melanomas with mutated RAS in mice. Melanomas with BRAF mutations were sensitive to inhibitors of the EGF receptor and AKT, which also restored sensitivity to vemurafenib.
"We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies," Held and colleagues conclude.