Eng , Christina, Wang, Zuncai, Tkach, Diane, Toral-Barzy, Lourdes, Ugwonali, Savuth, Liu, Shanming, Fitzgerald, Stephanie, George, Elizabeth, Frias, Elizabeth, Cochran, Nadire, Dejesus, Rowena, Mcallister, Gregory, Hoffman, Gregory, Bray, Kevin, Lemon, LuAnna, Lucas, Judy, Fantin, Valeria, Abraham, Robert, Murphy, Leon and Nyfeler, Beat (2016) Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. PNAS, 113 (1). pp. 182-187. ISSN 1091-6490

Abstract

Macroautophagy is a key stress response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, KRAS-driven tumors have been reported to rely on macroautophagy for growth and survival suggesting a potential therapeutic approach to use autophagy inhibitors based on genetic stratification. In this study, we evaluated if KRAS mutation status can predict the efficacy to inhibition of macroautophagy. By profiling 47 cell lines with pharmacological and genetic loss of function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of ATG7 by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knock out did not sensitize cells to irradiation or several anti-cancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the anti-proliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.

Item Type:	Article
Date Deposited:	27 Apr 2016 23:45
Last Modified:	27 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27646