Abstract
Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic.
Highlights
Cellular homeostasis is crucial for cell survival and refers to all processes involved in the maintenance of an internal steady state at the level of the cell
Compound 31 is a small molecule selective against protein and other lipid kinases [119]. All these four inhibitors are selective for PI3KC3, but it should be noted that vacuolar protein sorting 34 (VPS34) can form different complexes with other subunits that lead to a different localization and function, participating in vesicle trafficking [171]
In neuroblastoma cells, SBI-0206965 sensitizes cells to TNF-Related Apoptosis Inducing Ligand (TRAIL) treatment but not to mTOR inhibitors [100] indicating the non-protective role of autophagy in this model
Summary
Cellular homeostasis is crucial for cell survival and refers to all processes involved in the maintenance of an internal steady state at the level of the cell. Autophagy is one of the main catabolic mechanisms that contributes to cellular homeostasis, through the degradation and recycling of cytoplasmic components and organelles in the lysosomes [1,2] This process confers the ability to adapt to environmental stresses, preventing cellular damage, and promoting cell survival, even in starving conditions, having a main physiologic cytoprotective role. It is a process tightly regulated and its dysfunction has been related to several pathologies, such as neurodegeneration, cancer, or aging [3]. More than 120 clinical trials related to the process of autophagy were initiated to date The majority of those target autophagy for cancer treatment, already showing promising. Current strategies targeting autophagy for cancer treatment are summarized, highlighting combination therapies involving autophagy modulators that can sensitize cancer cells to conventional therapies, being able to overcome chemoresistance
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