A functional biomarker that can predict whether BRAF-mutant melanomas respond to drugs targeting BRAF could help guide the treatment of patients with these cancers, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19 - 23.
Approximately 50 percent of melanomas harbor mutations in the BRAF gene, and the U.S. Food and Drug Administration has approved two drugs that target BRAF for the treatment of such cancers. However, not all patients with BRAF-mutant melanomas respond to treatment with these, and most of those patients who initially respond eventually relapse because their tumors become resistant to the effects of the BRAF-targeted drugs.
"Our study has identified decreased phosphorylation of the protein S6 after treatment with BRAF-targeted drugs as a functional biomarker that predicts sensitivity of BRAF-mutant melanomas to these drugs," said Ryan B. Corcoran, M.D., Ph.D., a Damon Runyon clinical investigator and assistant professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, Mass. "Importantly, we have developed a minimally invasive way to rapidly monitor post-treatment changes in S6 phosphorylation in patients' tumor cells. As a result, we think that we can quickly determine whether or not a patient is likely to respond to a BRAF-targeted drug and help speed up treatment decisions, although we need to verify this in larger clinical studies."
BRAF gene mutations lead to inappropriate BRAF protein activity, which, in turn, causes a cascade of inappropriate activation of numerous other proteins in the tumor cell. Corcoran and colleagues therefore examined whether there were differences in the activity of the proteins downstream of BRAF in BRAF-mutant melanoma cell lines responsive and resistant to the BRAF-targeted drug vemurafenib.
They found that decreased phosphorylation of the protein S6 after treatment with vemurafenib was associated with responsiveness of BRAF-mutant melanoma cell lines to the drug both in vitro and in mice.