mTOR inhibitors in targeting autophagy and autophagy-associated signaling for cancer cell death and therapy

Abstract

The mechanistic target of rapamycin (mTOR) is a protein kinase that plays a central regulatory switch to control multifaceted cellular processes, including autophagy. As a nutrient sensor, mTOR inhibits autophagy by phosphorylating and inactivating key regulators, including ULK1, Beclin-1, UVRAG, and TFEB, preventing autophagy initiation and lysosomal biogenesis. It also suppresses autophagy-related protein expression, prioritizing growth over cellular recycling. Under nutrient deprivation, mTORC1 activity decreases, allowing autophagy to restore cellular homeostasis. Hyperautophagic activities lead to autophagic cell death; sometime after the point of no return, the cell goes for non-apoptotic, non-necrotic cell death i.e., Autosis. In cancer, the crosstalk between autophagy and mTOR is context-dependent, driving either cell survival or autophagy-dependent cell death. Using mTOR inhibitors, autophagic cell death can be induced to regulate cell growth, and proliferation is a potential therapeutic option for cancer treatment. mTOR inhibitors are broadly categorized into two types, i.e., natural and synthetic mTOR inhibitors. Although several studies in preclinical and clinical trials of various synthetic mTOR inhibitors are now in focus for cancer therapies, limited work has been done to explore autophagic cell death-inducing mTOR inhibitors. In addition, many natural mTOR inhibitors display better efficacy over synthetic mTOR inhibitors due to their lower toxicity, biocompatibility, and potential to overcome drug resistance in inducing autophagic cell death for cancer treatment.

Keywords: Autophagic cell death; Autophagy; Cancer therapy; mTOR inhibitors; mTOR signaling.