Abstract 6188: Exportin 1 inhibition synergizes with lurbinectedin by altering the response to DNA damage in neuroendocrine lung tumors
Authors: Resano Esther Redin , Rudin Charles , Quintanal-Villalonga Alvaro 
Published: April 2023

Abstract
Background: Neuroendocrine lung cancer carcinomas (Lung NECs), which include large cell neuroendocrine carcinomas (LCNECs) and small cell lung cancer (SCLC) tumors, are particularly aggressive lung neoplasms with limited clinical therapeutic options. Patients with lung NECs are treated with platinum-based chemotherapy as the first line of treatment, but they promptly develop resistance. Lurbinectedin has recently been approved by the FDA as a second-line treatment for SCLC due to its efficacy in metastatic chemorelapsed SCLC patients. However, there is still a large percentage of SCLC patients who do not respond to lurbinectedin and the overall survival of those who benefit from it remains very low (&lt;6 months). Previous work from our group had shown that exportin-1 (XPO1) was a driver of chemoresistance in SCLC and its inhibition with selinexor resentitized to first- and second-line chemotherapies in naïve and chemorelapsed SCLC patients derived xenografts, respectively. Importantly, selinexor is an FDA-approved drug for the treatment of relapsed multiple myeloma and is currently undergoing clinical testing in multiple solid tumors.
Methods: We performed synergy proliferation assays in vitro. DNA damage/repair pathways were analyzed by western blotting. Cell cycle and apoptosis were analyzed by flow cytometry.
Results: We explored the cytotoxic capacity of the combination of lurbinectedin with selinexor in cell linesfrom both SCLC (N=2) and LCNECs (N=3) in synergy in vitro assays. Selinexor strongly synergized with lurbinectedin in both SCLC and LCNEC settings and induced a potent increase in the DNA damage marker γ-H2A, reflective of increased DNA damage induced by the combination treatment. Mechanistically, this combination altered DNA damage and DNA repair mechanisms by decreasing CHK1 and CHK2 protein levels in short-term treatments, suggestive of the impairment of DNA response. Additionally, selinexor reduced the expression of MLH, a key regulator of DNA mismatch repair in monotherapy and in combination with lurbinectedin. Consistent with these results, selinexor in combination with lurbinectedin also induced a significant increase in apoptotic cells and promoted cell cycle arrest.
Conclusions: These data indicates that inhibition of exportin 1 with selinexor in combination with lurbinectedin is a promising therapeutic strategy in lung NECs. Subsequent In vivo testing in patient-derived xenograft to study efficacy and toxicity of this combination will provide preclinical rationale for clinically exploring this combination in patients with lung NECs who have failed chemotherapy regimen.
Citation Format: Esther Redin Resano, Charles Rudin, Alvaro Quintanal-Villalonga. Exportin 1 inhibition synergizes with lurbinectedin by altering the response to DNA damage in neuroendocrine lung tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6188.