Atg7 overcomes senescence and promotes growth of Braf^V600E-driven melanoma

TY - JOUR

T1 - Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma

AU - Xie, Xiaoqi

AU - Koh, Ju Yong

AU - Price, Sandy

AU - White, Eileen

AU - Mehnert, Janice M.

N1 - Publisher Copyright: © 2015 American Association for Cancer Research.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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 autophagyrelated- 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.

AB - 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 autophagyrelated- 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.

UR - https://www.scopus.com/pages/publications/84939508539

UR - https://www.scopus.com/pages/publications/84939508539#tab=citedBy

U2 - 10.1158/2159-8290.CD-14-1473

DO - 10.1158/2159-8290.CD-14-1473

M3 - Article

C2 - 25673642

SN - 2159-8274

VL - 5

SP - 410

EP - 423

JO - Cancer Discovery

JF - Cancer Discovery

IS - 4

ER -