title: Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma.
abstract: Macroautophagy (autophagy hereafter) may promote survival and growth of spontaneous tumors, including melanoma. We utilized a genetically engineered mouse model of melanoma driven by oncogenic BrafV600E and deficiency in the Pten tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene autophagy-related-7, Atg7. Atg7 deficiency prevented melanoma development by BrafV600E and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, BrafV600E-mutant, Pten-null, Atg7-deficient melanomas displayed accumulation of autophagy substrates and growth defects, which extended animal survival. Atg7-deleted tumors showed increased oxidative stress and senescence, a known barrier to melanomagenesis. Treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with Atg7 deficiency. Thus, Atg7 promotes melanoma by limiting oxidative stress and overcoming senescence, and autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors.
  
  
  CONCLUSIONS
  The essential autophagy gene Atg7 promotes development of BrafV600E-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAFV600E and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAFV600E/K mutations, an approach currently being explored in clinical trials.
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey.
authors: Xiaoqi
authors: X
authors: Xie
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey.
authors: Ju Yong
authors: JY
authors: Koh
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey.
authors: Sandy
authors: S
authors: Price
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey. mehnerja@cinj.rutgers.edu epwhite@cinj.rutgers.edu.
authors: Eileen
authors: E
authors: White
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey. mehnerja@cinj.rutgers.edu epwhite@cinj.rutgers.edu.
authors: Janice M
authors: JM
authors: Mehnert
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071193:Autophagy-Related Protein 7; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006579:Heterozygote; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; D000071193:Autophagy-Related Protein 7