Autophagy Modulation and Cancer Combination Therapy: A Smart Approach in Cancer Therapy.

The autophagy pathway is the process whereby cells keep cellular homeostasis and respond to stress via recycling their damaged cellular proteins, organelles, and other cellular components. In the context of cancer, autophagy is a dual-edge sword pro- and anti-tumorigenic role depending on the oncogenic context and stage of tumorigenesis. Cancer cells have a higher dependency on autophagy compared with normal cells because of cellular damages and high demands for energy. The carbon, nitrogen, and molecular oxygen are building blocks for highly proliferative cancer cells which extremely depend on glutaminolysis and aerobic glycolysis; when a cancer cell is restricted to glucose and glutamine, it initiates to activate a stress response pathway using autophagy. Oncogenic tyrosine kinases (OncTKs) and receptor tyrosine kinases (RTKs) activation result in autophagy modulation through activation of the PI3K/AKT/mTORC1 and RAS/MAPK signaling pathways. Targeted inhibition of tyrosine kinases (TKs) and RTKs have recently been considered as cancer therapy but drug resistance and cancer relapse continue to be a major limitation of tyrosine kinase inhibitors (TKIs). Manipulation of autophagy pathway along with TKIs may be a promising strategy to circumvent unknown existing drug-resistance mechanisms that may emerge in a treated patient. In this way, clinical trials are ongoing to modulate autophagy to treat cancer. This review aims to summarize the combination therapy of autophagy affecting compounds with anticancer drugs which target cell signaling pathways, metabolism mechanisms, and epigenetics modification to improve therapeutic efficacy against cancers.