The induction of PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells by a multispecific platinum complex

Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma (PDAC) cells to a state that is awfully resistant to apoptosis. An alternative coping strategy is to trigger a nonapoptotic cell death. Herein, a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin. Interestingly, SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis, apoptosis and necroptosis, similar to PANoptosis (a newfound inflammatory cell death). Mechanistically, SEP could enter cancer cells effectively, then damage nuclear DNA, boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor metabolism. To our best knowledge, SEP is the first metal complex, even small molecule, to elicit PANoptosis (pyroptosis, apoptosis and necroptosis) in cancer cells, providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.