By Bill Berkrot
Jan 15 (Reuters) - Researchers believe they have discovereda mechanism by which tumors eventually evade effectivecombination treatments for melanoma, providing clues that couldlead to longer-lasting therapies for the deadliest of skincancers.
The two-year study, led by Dr. Roger Lo of the UCLA JonssonComprehensive Cancer Center, looked at tumor samples from 15melanoma patients prior to therapy that combined a BRAFinhibitor with an MEK inhibitor and after they developedresistance to the drugs.
Previous research found that adding an MEK drug to a BRAFdrug significantly lengthened the time before the disease beganto worsen. That led to GlaxoSmithKline's Tafinlar andMekinist combination, and the combination of Roche's Zelboraf with the experimental Exelixis drugcobimetinib awaiting U.S. approval.
The so-called targeted therapies are designed to turn off specific molecular pathways associated with tumor growth. Theapproach can have dramatic effects, until tumor cells developresistance.
"The resistance is basically a matter of time, but if we figure out the strategies by which the resistance happens we canpropose new ways to suppress these mechanisms," Lo said in atelephone interview.
"If we can understand better what type of (genetic)mutations occur in melanoma ... we can design better and betterdrugs to suppress these. Either new drugs, better combinationsof drugs or better regimens of drugs," Lo said.
By studying genetic material from tumors that developedresistance to the combination therapy, Lo's team found highlyunusual changes in key cancer genes.
"What we found was genetic alterations were much moreexaggerated," Lo said.
"Most of the time when a gene is increased for the benefitof cancer, usually you see four copies, 10 copies," Lo said."Here, we're finding 80 or 100 copies.
"This is the result of a severe evolutionary pressureimposed on the cancer by the drugs. It's almost a signature ofresistance to the combo drug."
Along with the findings, published on Thursday in thejournal Cancer Cell, Lo's group proposed potential ways offighting the resistance, including intermittent therapy thatwould take a break from exposing the tumor to the drugs.
"Other ideas includes inhibitors that would inhibit certaintypes of signaling ... that specifically target mechanisms ofresistance," Lo said.
"We need to study iterative resistance to therapies so wecan construct better and better therapies to push the curve toincreased survival." (Editing by Bernadette Baum)