Researchers discover epigenetic reason for drug resistance in a deadly melanoma

(New York, NY - August 24, 2018)--Mount Sinai researchers have discovered a previously unknown reason for drug resistance in a common subtype of melanoma, one of the deadliest forms of cancer, and in turn, have found a new therapy that could prevent or reverse drug resistance for melanoma patients with a particular gene mutation, according to a study published in Nature Communications in August.

The 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, or a biological signature that accompanies 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 shows. 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," said 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."

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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.

The Mount Sinai Health System is New York City's largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 6,600 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 13 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke's and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.