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Separase Inhibition Enhances Gefitinib Sensitivity of Lung Cancer via PTBP1/TAK1/RIPK1-Mediated PANoptosis
Zhouyangfan Peng1, Liangpeng Xie1, Sufang Zhou2
1Health Management Center The Third Xiangya Hospital Central South University Changsha China.
Abstract:
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.
Insights
Separin inhibition with Sepin-1 enhances gefitinib
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Gefitinib is a primary lung cancer therapy, but drug resistance limits its effectiveness.
- Acquired resistance to gefitinib in lung cancer necessitates novel therapeutic strategies.
- Understanding resistance mechanisms is crucial for improving gefitinib efficacy.
Purpose of the Study:
- To investigate the potential of inhibiting separase to overcome gefitinib resistance in lung cancer.
- To explore the role of Sepin-1, a separase inhibitor, in enhancing gefitinib's anti-cancer effects.
- To elucidate the molecular mechanisms underlying Sepin-1 and gefitinib combination therapy.
Main Methods:
- Utilized lung cancer cell lines to assess gefitinib resistance.
- Employed the separase inhibitor Sepin-1 in combination with gefitinib.
- Conducted in vivo experiments using lung xenograft models.
- Analyzed molecular pathways involving PTBP1, TAK1, and RIPK1.
- Correlated clinical data with separase expression and PANoptosis markers.
Main Results:
- Sepin-1 significantly enhanced gefitinib-induced cytotoxicity by promoting PANoptosis (pyroptosis, apoptosis, necroptosis).
- Combination therapy led to significant regression of lung xenograft tumors in vivo.
- Mechanistically, combined treatment reduced PTBP1 and TAK1 expression, suppressing RIPK1 inactivation.
- Clinical data suggests lower separase or higher PANoptosis marker expression correlates with better gefitinib response.
Conclusions:
- Inhibiting separase with Sepin-1 is a promising strategy to overcome gefitinib resistance in lung cancer.
- The combination therapy induces tumor regression through a novel PANoptosis pathway.
- Separase inhibition represents a potential therapeutic target for enhancing gefitinib efficacy in lung cancer patients.
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