Autophagy Regulators: An Emerging Target in Melanoma

During the first plenary session on the second day of the Society for Melanoma Research, 2014 International Congress in Zurich, Switzerland, November 13-16, Targeted Therapies: Genetics and Biology, several researchers presented their thoughts on where they see the future of melanoma research. Various clinical issues faced while treating melanoma patients, including the optimal combination therapies and disease resistance to therapies, were discussed. Scientists also presented data and created a case for novel drug therapies in melanoma.

One of these presentations was by Janice Mehnert, MD, medical oncologist and interim director of the Phase I and Developmental Therapeutics Program, Rutgers Cancer Institute of New Jersey. Her presentation, “Atg7 overcomes senescence and promotes growth of BRAF-driven melanoma,” evauated Atg7 as a novel target in the treatment of B-Raf-mutated melanoma patient. Atg7 plays an important role in cell autophagy, and knockdown of this gene was shown to sensitize B-Raf wild type cells to death. This indicates a pro-survival role for autophagy in melanoma.

The process of cellular autophagy has several signaling pathways and components. Autophagy enables tumors to survive metabolic stress by recycling intracellular components to sustain metabolism. When the authors knocked down 2 of the components, Atg5 and Atg7, it impaired cell growth in multiple melanoma cell lines, demonstrating that these cancer cells depend on autophagy for their survival. There is a difference in cell sensitivity to Atg5 versus Atg7, indicating that some tumors rely more heavily on certain components of the pathway than others.

To test their hypothesis that inhibition of autophagy would enhance melanoma cell death, the authors used a genetically engineered mouse model with activated BRAFV600E and Pten-knockout in melanocytes. Atg7 loss in these mice prevented melanoma development by BRAFV600E and allelic Pten loss, suggesting that ATG7 and autophagy promote melanoma. Atg7 loss reduced melanoma growth and extended animal survival by 50%. Tumors with Atg7 loss accumulated LC3-I, p62, and abnormal mitochondria characteristic of autophagy defect. Next, the authors examined the role of Atg7 in senescence, a known barrier to melanoma. Atg7-deficient tumors were positive for senescence marker, consistent with upregulation of senescence. This in turn correlated with the induction of γ-H2X and 8-OXO-DG, markers of elevated oxidative stress. Dr Mehnert concluded that Atg7 promotes the growth of BRAFV600E- and Pten-null driven melanomas by limiting oxidative stress and overcoming the senescence barrier, and that autophagy inhibition may be of therapeutic value in the treatment of melanoma patients.