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Proc Natl Acad Sci U S A ; 113(1): 182-7, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26677873

ABSTRACT

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. 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 autophagy-related 7 (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 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative 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.


Subject(s)
Antineoplastic Agents/pharmacology , Autophagy/drug effects , Cell Transformation, Neoplastic/drug effects , Chloroquine/pharmacology , Drug Resistance, Neoplasm/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Autophagy/genetics , Autophagy-Related Protein 7 , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Erlotinib Hydrochloride/pharmacology , Gene Knockout Techniques , Humans , Indoles/pharmacology , Mutation , Protein Kinase Inhibitors/pharmacology , Pyrroles/pharmacology , Radiation Tolerance/genetics , Sunitinib , Ubiquitin-Activating Enzymes/genetics
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