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New Biomarker May Help Guide Treatment of Melanoma Patients

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Key Points

  • Decreased phosphorylation of the protein S6 after treatment with vemurafenib was associated with in vitro and in vivo responsiveness of BRAF-mutant melanoma cell lines to the drug.
  • After treatment with a BRAF-targeted drug, two-thirds of patients had lower levels of tumor cell S6 phosphorylation, which was associated with an almost fivefold improvement in progression-free survival.

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 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19 to 23 in Boston (Abstract C137).

Approximately 50% of melanomas harbor mutations in the BRAF gene, and the U.S. Food and Drug Administration has approved two drugs that target BRAF—vemurafenib (Zelboraf) and dabrafenib (Tafinlar)—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 targeted drugs.

S6 Phosphorylation

“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, MD, PhD, a Damon Runyon Clinical Investigator and Assistant Professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston. “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.”

Study Details

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. Dr. 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 levels of S6 phosphorylation in tumor cells in real time. 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 2 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 Dr. 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.”

This study was funded by a Damon Runyon Clinical Investigator Award, the National Institutes of Health, and the National Cancer Institute.

Dr. Corcoran reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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