Abstract 1166: Lurbinectedin synergizes with selinexor by inhibiting DNA damage repair and enhancing immune cell infiltration in neuroendocrine lung and prostate tumors

Abstract Large cell (LCNEC), prostate (NEPC) and small cell lung (SCLC) neuroendocrine carcinomas are highly aggressive malignancies with few therapeutic options. Lurbinectedin, is an FDA-approved DNA-damaging agent used for the treatment of SCLC, although its efficacy remains limited. Our group has found that neuroendocrine (NE) tumors have higher levels of DNA damage repair (DDR) proteins than non-NE tumors, which may contribute to their reduced response to DNA-damaging agents. Exportin 1 (XPO-1), is an export receptor that regulates DDR proteins, and it can be inhibited with selinexor. We have explored the combination of lurbinectedin with selinexor as a potential strategy for treating neuroendocrine tumors. XPO-1 was found significantly upregulated in neuroendocrine carcinomas (NECs) biospecimens compared to normal tissues, and its expression positively correlated with DDR genes such as CHEK1, WEE1 and PARP1. Combination of selinexor and lurbinectedin demonstrated a potent synergistic effect in SCLC, LCNEC and NEPC cell lines and significantly enhanced apoptosis compared to single-agent treatments. RNA sequencing (RNAseq) analysis revealed a pronounced induction of DNA damage, alongside a reduction in DNA repair pathways in double treated cells compared to untreated cells. Western blotting confirmed increased levels of γ-H2AX and cleaved PARP, while showing decreased expression of CHK1, CHK2, and MLH1. Comet assays further demonstrated increase in DNA strand breaks in cells treated with the combination compared to monotherapies. We next evaluated the efficacy of this combination therapy in patient-derived xenograft (PDX) models, including two SCLC, two LCNEC, and one NEPC model. The combination significantly suppressed the tumor growth of three chemoresistant PDXs while delayed tumor relapse in another two naïve models. Furthermore, the dual treatment activated both STING and autophagy pathways, as evidenced by the increased levels of mTOR and LC3B-I/II in vitro. RNA sequencing analysis revealed the upregulation of inflammatory and interferon-γ (IFN-γ)-related pathways, indicating that this therapeutic combination may have an immunomodulatory effect. Consistent with this, the combination of selinexor and lurbinectedin showed strong synergy in a Rb1−/−; Trp53−/−; cMyc+ (NEPC) and a Rb1−/−; Trp53−/−; Rb2−/− (SCLC) triple mutant mouse models, both resistant to either treatment alone. Single-cell RNAseq of these models revealed increased infiltration of immune cells (CD45+ cells), along with enhanced antigen presentation in tumors treated with either lurbinectedin alone or in combination. Furthermore, treatment with lurbinectedin or the combination, enhanced the infiltration of T cells, monocytes, and macrophages into the tumor. In summary, selinexor and lurbinectedin is a promising strategy for targeting NE tumors. Citation Format: Esther Redin, Parvathy Manoj, Juan Qiu, Barbara de Mello, Hong Zhong, Suleyman Vural, Yingqian Zhan, Rodrigo Romero, Nicholas Socci, Richard Koche, Charles Sawyers, Elisa de Stanchina, Charles M Rudin, Alvaro Quintanal-Villalonga. Lurbinectedin synergizes with selinexor by inhibiting DNA damage repair and enhancing immune cell infiltration in neuroendocrine lung and prostate tumors [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 1166.