Journal Club

Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

Science Translational Medicine - 11 Jan 2023 - Vol 15, Issue 678

Putting back pyroptosis While chemotherapeutic drugs are the standard of care for several cancers, patients often develop resistance to apoptotic directed cell death. Pyroptosis, a gasdermin dependent programmed necrotic death, offers a potential target to overcome this chemoresistance. Su et al. have determined that beta 5-integrin represses chemotherapy-induced canonical pyroptosis to induce chemoresistance mediated by sphingolipid metabolic reprogramming. This pathway upregulates the sphingolipid metabolic enzyme ceramidase (ASAH2) that when inhibited in vivo was able to resensitize xenografts to chemotherapy. These results suggest pyroptosis-based therapy as a potential treatment to overcome chemotherapy resistance and warrants further investigation.

Abstract Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src–signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.