Separase Inhibition Enhances Gefitinib Sensitivity of Lung Cancer via PTBP1/TAK1/RIPK1‐Mediated PANoptosis

Gefitinib is the most frequently employed anti-lung cancer drug, but its clinical effectiveness is often compromised due to the development of drug resistance. Given that gefitinib failure to long-term inhibition of the growth of lung carcinoma cell lines, which mirrors the resistance observed in clinical patients, new approaches to improve the curative effect of gefitinib should be found. Surprisedly, inhibiting separase with the specific inhibitor Sepin-1 has been found to effectively enhance gefitinib-induced cytotoxic in lung cancer cell by promoting the development of PANoptosis, which includes pyroptosis, apoptosis, and necroptosis. Moreover, in vivo experiments also demonstrated that the combination of Sepin-1 and gefitinib can induce significant regression of lung xenograft tissues. Mechanically, loss of separase plus gefitinib decreases the expression of PTBP1 and TAK1. Overexpression of PTBP1 or TAK1 suppresses this interaction-induced PANoptosis by promoting the inactivation of RIPK1. In addition, clinical data showed that better effective of gefitinib maybe associated with lower separase expression or higher PANoptosis marker expression in patient lung carcinoma tissues. Thus, these findings provide a novel anti-lung cancer strategy and highlight separase as a potential target for overcoming gefitinib resistance in lung cancer treatment.