Inhibition of Autophagy by Targeting ATG4B: Promises and Challenges of An Emerging Anti-cancer Strategy

Aside from its function in cellular homeostasis, autophagy enables cells to dispose of damaged cellular components and to recycle metabolites in response to cellular stress. Of particular interest is the context-dependent role of autophagy in cancer. Autophagy has been shown to inhibit tumor growth in the early stages of carcinogenesis, yet promotes the progression of previously established tumors. The characterization of potent, specific autophagy inhibitors with novel mechanisms of action is a very active area of research. ATG4B is one of four mammalian ATG4 orthologues and cleaves the ubiquitin-like ATG8 mammalian orthologues (e.g. pro-LC3B), a crucial step in the formation of the mature autophagosome. This review provides an overview of the role of ATG4 orthologues during autophagy, describes cancerspecific ATG4 functions and discusses the role of ATG4B inhibition as an emerging anti-cancer strategy. While available data show that impairing ATG4B typically decreases the growth of human cancer cell lines in vitro and in vivo, under certain circumstances ATG4B inhibition may also be detrimental. On the other hand, pre-clinical testing of ATG4B inhibitors and the analysis of ATG4B knockout mice suggest that ATG4B inhibition should be very well tolerated. As is the case with other autophagy inhibitors, future studies would benefit from the development of suitable predictive biomarkers of response and tools to monitor autophagy activity.