This article is more than 5 years old. Information may no longer be current.
Drug screening identified possible combination therapies for mutant BRAF, RAS melanomas
Click Here to Manage Email Alerts
Researchers used combinatorial drug screening to identify potential treatment regimens, including statins and cyclin-dependent kinase inhibitors, for mutant BRAF- and RAS-driven melanomas, according to recent study results.
“The identification of gene mutations that drive specific subsets of [some] cancers has had a major beneficial impact on treatments for these patients,” researcher David F. Stern, PhD, professor of pathology at Yale University School of Medicine, said in a press release from the American Association for Cancer Research. “Some patients who have 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.”
Researchers analyzed 150 small-molecule compounds, including chemotherapies and targeted anticancer agents, and selected 40 single agents to use in combination high-throughput screening. Several inhibitor combinations displayed effectiveness for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. When both EGF receptor and AKT were inhibited, treatment-resistant BRAF mutant melanoma cultures developed sensitivity to vemurafenib.
“Perhaps the most interesting observation was that several drug combinations that included a statin killed RAS-driven melanoma cell lines,” Stern said.
Melanomas with RAS mutations showed sensitivity to statins and cyclin-dependent kinase inhibitors combined in vitro and in vivo, but were more resistant to other combination therapies compared with BRAF mutants.
Simvastatin combined with flavopiridol, which inhibits proteins that activate cell division, showed efficacy in vitro and also worked in vivo to substantially reduce RAS-driven human melanoma cell line growth when transplanted into mice, according to the release.
“Cancers associated with poor prognoses, such as advanced-stage melanomas, will require combination therapies to obstruct the outgrowth of resistant cells,” the researchers concluded. “Combinatorial drug screening has allowed for the discovery and experimental confirmation of a number of effective combination regimens that in the correct genotypic setting may prove more effective and tolerable in patients while avoiding selection for resistance through inadequate dosing.”
Click Here to Manage Email Alerts