title: Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.
abstract: Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA; University of Colorado Comprehensive Cancer Center; Aurora, CO USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morgan
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Graciela
authors.initials: G
authors.lastname: Gamez
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Menke
authors.affiliation: University of Colorado School of Medicine; Medical Scientist Training Program; Aurora, CO USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Thorburn
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Freddi
authors.initials: F
authors.lastname: Gidan
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Staskiewicz
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Shellie
authors.initials: S
authors.lastname: Morgan
authors.affiliation: University of Colorado School of Medicine; Medical Scientist Training Program; Aurora, CO USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cummings
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Maycotte
authors.affiliation: Department of Pharmacology; University of Colorado School of Medicine; Aurora, CO USA; University of Colorado Comprehensive Cancer Center; Aurora, CO USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D009857:Oncogenes; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D002738:Chloroquine; D018631:ras Proteins
keywords: RAS; autophagy; autophagy dependence; cell death; chloroquine