Targeting autophagy to overcome drug resistance: further developments

Abstract

Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.

The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment

“…Given the heterogeneous nature of breast neoplasms and the fact that cancer treatment may require long-term administration of certain autophagy modulators, there is a great need to foster research on biomarkers to monitor autophagy status in vivo upon novel combination treatments. It is important to keep in mind that autophagy can modify tumor immune responses as well [207][208][209][210]. Altogether, identifying and validating biomarkers for active autophagy and the use of specific autophagy modulating drugs might enable researchers and medical oncologists to predict the effects of early versus late autophagy modulation for personalized breast cancer care.…”

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…Autophagy is the controlled removal of unnecessary or dysfunctional components from cells, enabling the recycling of cellular components [ 329 ]. Although autophagy has tumor-suppressive roles in normal cells by removing damaged organelles [ 330 ], it also protects cancer cells from cell death [ 331 , 332 ]. Mounting evidence further supports the idea that drug-induced autophagy causes resistance of cancer cells, and combined inhibition of autophagy is a plausible strategy to overcome this resistance [ 331 , 332 , 333 ].…”

“…As mentioned earlier, autophagy has been established as a novel mechanism and therapeutic target to overcome anticancer drug resistance [ 331 , 332 , 333 ]. EGFR TKIs have been reported to activate autophagy as a cytoprotective response in various cancer cell lines, including breast cancer [ 333 ], lung cancer [ 573 , 574 ], squamous cell carcinoma, and transitional cell carcinoma [ 337 ].…”

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

“…It has been stated that the main downstream of PI3K/AKT leads to autophagy inhibition. Thus, the combination of PI3K inhibition with autophagy inhibition can achieve a more potent anti-tumor effect and cell cycle-mediated drug resistance [10]. Therefore, crosstalk between autophagy inhibition and apoptosis-induction in many cancer cells is considered a therapeutic strategy to sensitize tumor cells and overcome resistance.…”