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.

The epithelial polarity regulator LGALS9/galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux

“…32 However, cancers which harbor RAS mutations are not always sensitive toward treatment with autophagy inhibitors, and the expression of oncogenic RAS may even promote resistance toward autophagy inhibition in lung cancer cell lines. 33 Therefore, the relation between KRAS mut expression and sensitivity toward rLGALS9, may be specific for colon cancer. Besides the maintenance of tumorigenesis, the activation of autophagy is one of the mechanisms by which tumor cells acquire therapy resistance.…”

Autophagy mediates oral submucous fibrosis

“…The activation of the autophagy pathway and its potent profibrotic effects suggest that autophagy may be a potential target for novel antifibrotic approaches. In the present study the autophagy inhibitor CQ was selected for the inhibition of the autophagy pathway for the following reasons: Firstly, it is able to diffuse across cell membranes, undergo protonation and accumulate in acidic organelles, such as lysosomes (29); secondly, it is a 4-aminoquinoline drug used in the treatment of numerous diseases; and thirdly, this approach allows broader inhibition of autophagy compared with targeting single autophagy proteins (30).…”

Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers

“…Given that autophagy plays context-dependent roles in cancer, the clinical benefits of targeting autophagy may be unpredictable. Consistent with this concern, a recent study showed that RAS mutation status alone might be insufficient to predict autophagy addiction and CQ sensitivity of cancer cells cultured in vitro (18). Hence, there is a need to define the optimum cellular contexts or identify new biomarkers that will aid in the therapeutic targeting of autophagy via lysosomotropic agents such as CQ or HCQ.…”