2024 World Conference on Lung Cancer (WCLC) - Posters-P1.03G.01 Lurbinectedin Synergizes with Selinexor by Inhibiting DNA Damage Repair and Enhancing Immune Cell Infiltration in Neuroendocrine Lung Tumors

P1.03G.01 Lurbinectedin Synergizes with Selinexor by Inhibiting DNA Damage Repair and Enhancing Immune Cell Infiltration in Neuroendocrine Lung Tumors

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The study investigates the combination of Lurbinectedin and Selinexor as a therapeutic strategy for treating aggressive lung neuroendocrine carcinomas (NECs), such as large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). Patients with these types of cancer often develop resistance to platinum-based first-line chemotherapy, with Lurbinectedin being an FDA-approved second-line treatment. However, many patients do not respond to Lurbinectedin alone.<br /><br />The research highlights the synergistic effect of Selinexor, an exportin-1 (XPO1) inhibitor, when combined with Lurbinectedin. This combination therapy enhances the induction of DNA damage and inhibits repair mechanisms in both SCLC and LCNEC cell lines. The dual treatment also led to increased apoptosis, cell cycle arrest, and activated pathways associated with autophagy and immune response, including the STING and mTOR pathways. Furthermore, the combination showed significant synergy in chemorelapsed SCLC and LCNEC patient-derived xenografts (PDXs) and an Rb1/Tp53 mutant mouse model that resisted treatment with either agent alone.<br /><br />The study further noted an increase in immune cell infiltration and antigen presentation in tumor models treated with the combination, suggesting enhanced immune activation. The synergistic effect was supported by high HSA synergy scores in vitro and significant reductions in tumor volume in vivo mouse models. <br /><br />Overall, the data suggests that co-administering Selinexor with Lurbinectedin offers a promising approach to overcoming resistance and improving clinical outcomes in NEC cases, potentially paving the way for new treatment protocols. The study emphasizes the need for further investigation into the molecular pathways activated by this drug combination and its potential therapeutic benefits.

Asset Subtitle

Esther Redin

Meta Tag

Speaker Esther Redin

Topic Tumor Biology – Translational Biology

Keywords

Lurbinectedin

Selinexor

neuroendocrine carcinomas

lung cancer

chemotherapy resistance

synergistic effect

DNA damage

immune activation

tumor models

treatment protocols