Novel Epigenetic Mechanism May Cause Drug Resistance in Melanoma

New research sheds light on epigenetic reason for drug resistance in melanoma, and identifies potential therapies that may prevent such resistance, according to a paper in Nature Communications.

Mount Sinai researchers identified a novel epigenetic mechanism that causes resistance to the standard treatment in melanoma patients with mutations in the BRAF genes, which are found in about half of all melanomas. Researchers also found a biomarker for this drug resistance: a gene called IGFBP2, which is also associated with poor prognosis in melanoma patients.

Patients with high levels of IGFBP2 could benefit from combination therapies, which could be created in response to these findings, that inhibit BRAF mutations and IGFBP2-driven biological pathways as a multi-pronged approach to preventing drug resistance or reversing it once it has occurred, the study suggests. Other studies show the potential to find IGFBP2 via urine samples so the implications for detection and later treatment are large.

“The incidence of cutaneous malignant melanoma is rising and its therapeutic management remains challenging,” says lead researcher Emily Bernstein, PhD, Associate Professor of Oncological Sciences and Dermatology at the Icahn School of Medicine at Mount Sinai. “In recent years, there has been extensive therapeutic development to inhibit key biological targets. Although a large proportion of patients with advanced metastatic melanoma harboring BRAF mutations respond to the standard therapy, known as MAPK inhibitors, subsequent resistance remains a major clinical challenge.”

This research was funded by La Roche-Posay North American Foundation, American Skin Association, Pershing Square Sohn Cancer Research Alliance, and the U.S. Department of Defense.