Targeting Autophagy to Treat Cancer: Challenges and Opportunities

Abstract

Autophagy is a catabolic process that targets its cargo for lysosomal degradation. In addition to its function in maintaining tissue homeostasis, autophagy is recognized to play a context-dependent role in cancer. Autophagy may inhibit tumor initiation under specific contexts; however, a growing body of evidence supports a pro-tumorigenic role of this pathway in established disease. In this setting, autophagy drives treatment resistance, metabolic changes, and immunosuppression both in a tumor-intrinsic and extrinsic manner. This observation has prompted renewed interest in targeting autophagy for cancer therapy. Novel genetic models have proven especially insightful, revealing unique and overlapping roles of individual autophagy-related genes in tumor progression. Despite identification of pharmacologically actionable nodes in the pathway, fundamental challenges still exist for successful therapeutic inhibition of autophagy. Here we summarize the current understanding of autophagy as a driver of resistance against targeted and immuno-therapies and highlight knowledge gaps that, if addressed, may provide meaningful advances in the treatment of cancer.

Keywords: agy; autoph; cancer; immunology; immunotherapy; oncology.

FIGURE 1

Actionable nodes of the autophagy pathway. The process of autophagy begins with generation of the initiation complex. Its substrates include factors critical for phagophore nucleation. This is also called the Vps34 complex and is involved in initiation of autophagy as well as endosome maturation. The lipid kinase activity of Vps34 generates PI3P on the target membrane, forming the omegasome upon which the autophagy nucleation complex forms. The ER is depicted as a membrane source for the omegasome, but other membranous compartments have also been described. The autophagy elongation machinery includes an E1-E2-E3-like process that ultimately results in lipidation of ATG8 family proteins, thereby identifying a mature autophagosome. Two conjugation systems are illustrated: the ATG8 conjugation system (red) transfers LC3/ATG8 to the E2-like protein ATG3. The ATG12 conjugation system (green) generates the E3-like complex by transferring ATG12 onto ATG5. Association of the ATG5-12 fusion with ATG16L1 forms the ATG16L1 complex; this acts in an E3-like manner to transfer ATG8/LC3 onto phosphatidyl ethanolamine (PE), thereby completing the lipidation process. Cysteine proteases of the ATG4 family cleave ATG8/LC3 from the cytosolic face of the autolysosome for re-use. ATG4 family proteins are critical in the initial activation of ATG8/LC3 by exposing the C-terminal glycine for conjugation. As depicted, several members of core autophagy machinery have been assessed in genetic and pharmacological models for their role in cancer biology. Additional details of genetic models are provided in Table 1. A more extensive list of pharmacological inhibitors is provided in Table 2. Created with BioRender.com.