Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy

• DOI: 10.1073/pnas.1515617113
• Publication Date: 2015-12-18T01:49:44Z
• Authors: Christina H. Eng; Zuncai Wang; Diane Tkach; Lourdes Toral-Barza; Savuth Ugwonali; Shanming Liu; Stephanie L. Fitz...; Elizabeth George; Elizabeth Frias; Nadire Cochran; Rowena De Jesus; Gregory McAllister; Gregory R. Hoffman; Kevin Bray; LuAnna Lemon; Judy Lucas; Valeria R. Fantin; Robert T. Abraham; Leon O. Murphy; Beat Nyfeler
• Keywords: 0301 basic medicine; Indoles; Antineoplastic Agents; Chloroquine; Ubiquitin-Activating Enzymes; Autophagy-Related Protein 7; Radiation Tolerance; 3. Good health; Proto-Oncogene Proteins p21(ras); Erlotinib Hydrochloride; Gene Knockout Techniques; 03 medical and health sciences; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Cell Line, Tumor; Mutation; Autophagy; Sunitinib; Humans; Pyrroles; Protein Kinase Inhibitors; Cell Proliferation

Significance Kirsten rat sarcoma (KRAS) mutant tumors are believed to depend on autophagy for growth and survival. This study details the unexpected finding that autophagy-related 7, an enzyme essential for macroautophagy, can be deleted in several KRAS-driven cancer lines without affecting growth in vitro or in vivo. These data indicate that KRAS mutation status does not predict cell-autonomous addiction to autophagy. Furthermore, this report addresses a long-standing question regarding the mechanism of chloroquine, a lysosomotropic agent often used to interrogate effects of autophagy inhibition. Although chloroquine is antiproliferative and synergizes with targeted anticancer drugs, these effects are independent of macroautophagy. Future studies are needed to identify appropriate genetic stratification parameters to predict efficacy toward chloroquine and to characterize such agents further as anticancer combination partners.