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.
They then analyzed S6 phosphorylation in tumor biopsies obtained from nine patients with BRAF-mutant melanomas before and after they had initiated treatment with a BRAF-targeted drug. Six patients had lower levels of tumor cell S6 phosphorylation after treatment compared with before treatment, and this was associated with an almost fivefold improvement in progression-free survival.
Finally, the researchers evaluated a method to rapidly monitor, in real time, levels of S6 phosphorylation in tumor cells. They found that they could reliably assess levels of S6 phosphorylation in tumor cells in fine-needle aspiration biopsies from patients before and during the first two weeks of treatment with a BRAF-targeted drug, and that in these patients, a decrease in S6 phosphorylation after treatment correlated with treatment response.
"Many of the signaling pathways known to drive various types of cancer regulate phosphorylation of S6, not just the BRAF pathway," said Corcoran. "Therefore, we are investigating whether S6 phosphorylation could be a biomarker of response to therapies that target these pathways in cancers other than melanoma."