Abstract
Autophagy is an evolutionary conserved stress survival pathway that has been shown to play an important role in the initiation, progression, and metastasis of multiple cancers; however, little progress has been made to date in translation of basic research to clinical application. This is partially due to an incomplete understanding of the role of autophagy in the different stages of cancer, and also to an incomplete assessment of potential drug targets in the autophagy pathway. While drug discovery efforts are on-going to target enzymes involved in the initiation phase of the autophagosome, e.g., unc51-like autophagy activating kinase (ULK)1/2, vacuolar protein sorting 34 (Vps34), and autophagy-related (ATG)7, we propose that the cysteine protease ATG4B is a bona fide drug target for the development of anti-cancer treatments. In this review, we highlight some of the recent advances in our understanding of the role of ATG4B in autophagy and its relevance to cancer, and perform a critical evaluation of ATG4B as a druggable cancer target.
Highlights
Autophagy is a cellular stress response that has been identified as a target pathway for intervention in various diseases such as neuro-degenerative disorders, pathogen infection, and various types of cancer [1]
We propose that human ATG4B is a druggable target with strong potential for the development of potent inhibitors
There is clear evidence that targeting ATG4B can provide a benefit in cancer, and there is good evidence for breast cancer, lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma
Summary
Autophagy is a cellular stress response that has been identified as a target pathway for intervention in various diseases such as neuro-degenerative disorders, pathogen infection, and various types of cancer [1]. It has been noted that ATG5 defective cells can induce the formation of spontaneous liver tumours [5] Since these are mostly benign adenomas, it was suggested that progression to a malignant state may be dependent on autophagy [6]. Members of the LC3/GABARAP family can be phosphorylated by Tank-binding kinase 1 (TBK1), which renders them resistant to ATG4-mediated deconjugation [16] These post-translational mechanisms of regulation suggest a spatio-temporal control of key autophagy genes to enable completion of autophagosome maturation. Both academic labs and pharmaceutical companies have proposed and explored the possibility to develop small molecule inhibitors for targeting autophagy in cancer This has been done using phenotypic screening trying to block the formation or fusion of auto-lysosomes [22,23], which has been very successful in identifying research tool compounds for investigating the pathway in more detail. We will perform a critical appraisal of ATG4B as drug target in cancers and discuss tools and reagents available for drug development
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