Lys-ing the Resistance: Targeting Lysosomes to Overcome Chemoresistance in Ovarian Cancer

For decades, ovarian cancer (OC) therapy has mainly relied on a regimen of tumor resection followed by treatment with cisplatin and paclitaxel. While this treatment is usually effective initially, resistance to this regimen in OC is widespread and is often the cause of death in OC patients. In the attempt to find new molecular targets for the treatment of chemoresistant OC, understanding the precise mechanisms of chemoresistance remains a paramount task. This review examines the critical roles of the lysosome in the instigation of chemoresistance in OC and explores possible clinical applications for overcoming chemoresistance.

Lysosomes contribute to chemoresistance through various mechanisms, including increased lysosomal biogenesis, resulting from the enhanced activity of transcription factor EB, a master regulator of the autophagy-lysosome pathway, which enhances cellular capacity for drug sequestration. Lysosomal exocytosis allows the cell to secrete chemotherapeutic agents from OC cells. Lysosomal autophagy pathways enable OC cells to selectively recycle cell components during chemotherapeutic stress. Finally, lysosomal signaling pathways disrupt various cell death mechanisms such as apoptosis, necroptosis, and ferroptosis, which allow cancer cells to evade death under chemotherapeutic stress. Targeting lysosomal biogenesis, stage-specific autophagy modulation, and lysosome-dependent metabolic vulnerabilities are promising avenues for sensitization of chemoresistant OC cells.