Half of all melanomas harbor an activating mutation in the BRAF gene that turns on the cancer signaling pathway in cells known as the MAP kinase pathway. Activation of the MAP kinase pathway promotes tumor growth and survival. Drugs designed to selectively block activated BRAF have led to significant improvement in clinical response and overall survival in melanoma patients, but resistance to these drugs often develops – leading to recurrence. With this study, published in the current online edition of Cancer Discovery (doi: 10.1158/2159-8290.CD-14-1473), senior author Janice M. Mehnert, MD, medical oncologist in the Melanoma and Soft Tissue Oncology Program at the Cancer Institute of New Jersey, in collaboration with Eileen White, PhD, associate director for basic science at the Cancer Institute and distinguished professor of molecular biology and biochemistry at Rutgers School of Arts and Sciences, aimed to identify mechanisms critical for melanoma that could be targeted in conjunction with BRAF inhibition.
Investigators tested the consequence of removing the autophagy gene known as ATG7 from laboratory models of BRAF-driven melanoma. Autophagy is a process in which intracellular components are recycled in order to help sustain cell growth. When ATG7 was removed from melanomas they found much smaller tumors with increased senescence, which is a known barrier to cancer that causes tumor cells to stop proliferating. Thus ATG7 promotes development of BRAF-mutated melanoma by overcoming senescence. They went on to show that loss of ATG7 potentiated the anti-tumor activity of a BRAF inhibitor in melanoma. The work demonstrates that BRAF-mutated melanoma requires autophagy for tumor development and blocking autophagy could have therapeutic value, particularly in combination with BRAF inhibition.
“This discovery that ATG7 promotes the growth of melanoma tumors underscores that the development of agents targeting autophagy may effectively inhibit melanoma growth,” notes Dr. Mehnert, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School. Clinical trials seeking to block the process of autophagy are ongoing at the Cancer Institute.
Other authors on the study include: Xiaoqi Xie, Ju Yong Koh and Sandy Price, all Cancer Institute and Robert Wood Johnson Medical School.
The work was supported by funding from the V Foundation for Cancer Research, National Institutes of Health (R01CA163591, R01CA130893), the Val Skinner Foundation and Rutgers Cancer Institute of New Jersey (pilot grant P30CA072720).
About Rutgers Cancer Institute of New JerseyRutgers Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, the Cancer Institute of New Jersey is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention. Physician-scientists at the Cancer Institute engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support the Cancer Institute of New Jersey, call 848-932-3637 or visit www.cinj.org/giving. Follow us on Facebook at www.facebook.com/TheCINJ.
The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Medical Center and Carol G. Simon Cancer Center at Overlook Medical Center. Affiliate Hospitals: JFK Medical Center, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), and Robert Wood Johnson University Hospital Somerset.
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