Atg7 Overcomes Senescence and Promotes Growth of BrafV600E-Driven Melanoma

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 Braf(V600E) 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 Braf(V600E) and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, Braf(V600E)-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. SIGNIFICANCE: The essential autophagy gene Atg7 promotes development of Braf(V600E)-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAF(V600E) and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAF(V600E/K) mutations, an approach currently being explored in clinical trials. (C)2015 AACR.