Abstract 2895: Efficacy of DNA-PK inhibitor as maintenance strategy after cisplatin induction in SCLC

Abstract Given the aggressive nature of small cell lung cancer (SCLC) and the frequent relapse after initial chemotherapy, this work aims to identify novel approaches to enhance the immune response. DNA-dependent protein kinase (DNA-PK) is a targetable enzyme involved in non-homologous end joining (NHEJ) and antiviral responses. DNA-PK plays a role during cGAS/STING dependent and independent viral DNA sensing pathway. Thus, we investigated the role of DNA-PK inhibition (DNA-PKi) as a maintenance strategy following cisplatin treatment in SCLC patients, focusing on its ability to enhance antitumor immune responses. We included different models of SCLC, in particular SCLC patient-derived peripheral blood mononuclear cells (PBMCs), SCLC cell lines and cocultures of PBMCs with SCLC cells and SCLC tumor spheroids. SCLC cells were treated in vitro with low-dose cisplatin (0.5 µM), and blood was collected from SCLC patients on day 3 of cisplatin treatment. SCLC cells and PBMCs were subjected to transcriptomic sequencing and gene expression profiling to assess the effect of DNA-PKi on PBMC subsets (CD8+ T cells, NK cells and monocytes). Gene set enrichment analysis (GSEA) of RNA-seq data revealed that cisplatin treatment enriched several DDR pathways and upregulated immune-related pathways in both SCLC cell lines and patient-derived PBMCs. Sequential treatment with DNA-PKi after cisplatin significantly activated CD8+ T-cell and NK-cell pathways, as well as enhancing interferon-related pathways and gene signatures associated with viral infections. In vitro treatment with DNA-PKi resulted in increased expression of pro-inflammatory markers in PBMCs, promoting M1 polarization of macrophages (TNF-α, IL-6 and CXCL10) while inhibiting M2 polarization (IL-10, IL4 and CCL22). This shift towards an anti-tumor phenotype was confirmed by enhanced NK cell-mediated cytotoxicity against SCLC cell lines. In addition, combination therapy with DNA-PKi and anti-PD-L1 resulted in increased immune cell infiltration into tumor spheroids, demonstrating a synergistic effect on anti-tumor immunity. In conclusion, our data suggests that DNA-PKi may improve immune responsiveness and potentially prolong antitumor effects in SCLC patients. Future investigations are warranted to further elucidate these mechanisms and to evaluate the clinical applicability of DNA-PKi in combination with existing therapies for SCLC. Citation Format: Luisa Amato, Caterina De Rosa, Concetta Tuccillo, Francesca Iommelli, Viviana De Rosa, Virginia Tirino, Federica Papaccio, Kavya Ramkumar, Qi Wang, Jing Wang, Alberto Servetto, Floriana Morgillo, Lauren Averett Byers, Fortunato Ciardiello, Carminia Maria Della Corte. Efficacy of DNA-PK inhibitor as maintenance strategy after cisplatin induction in SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2895.