Abstract 3594: Exportin 1 inhibition as a therapeutic strategy for small cell lung cancer
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirokazu , Hao Yuan , Chow Andrew , Zhan Yingqian A. , Uddin Fathema , Allaj Viola , Manoj Parvathy , Shah Nisargbhai S. , Bhanot Umesh K. , Qiu Juan , de Stanchina Elisa , Koche Richard P. , Sen Triparna , Poirier John T. , Rudin Charles M. 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is an aggressive disease characterized by early metastasis and exceptional lethality, comprising 13% of all lung cancer cases. With few treatment options, typically resulting in only transient responses, SCLC is responsible for approximately 250,000 deaths globally per year. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy to first-line chemotherapy showing limited benefit in a small subset of patients. Major hurdles to improving SCLC treatment include development of rapid chemoresistance and ineffective second line therapies. The identification of more durably effective therapeutic strategies is a major unmet clinical need. Here, we performed an in vitro CRISPR screen in SCLC cell lines from all major SCLC subtypes, including short-term cultured cells from patient-derived xenografts (PDXs), to identify potential therapeutic targets to enhance sensitivity to chemotherapy. Candidate hits were validated genetically and pharmacologically with in vitro synergy assays, in vivo clonal competition assays and pharmacologic assessments in PDX models. Signaling pathways were studied by RNA sequencing and western blot, and toxicity studies were performed in vivo to assess the safety of the agents at pharmacologically effective doses. We performed immunohistochemistry (IHC) to assess expression of candidate targets in tissue microarrays (TMAs). Our CRISPR screen revealed the nuclear exporter exportin 1 (encoded by the XPO1 gene) as a promising target sensitizing to chemotherapy, independently of the SCLC subtype. We found that XPO1 mRNA expression was higher in SCLC than in any other solid tumor or hematological malignancy, and demonstrated consistently high protein expression by IHC in clinical TMAs. A potent and selective exportin 1 inhibitor, selinexor, is approved for use in hematological malignancies. Combination of selinexor with cisplatin or irinotecan demonstrated synergy in vitro and efficacy in vivo in an array of chemonäive and chemoresistant SCLC PDXs, including all major SCLC subtypes. The combinations were well tolerated in mice. The chemo-sensitizing effects of selinexor were associated with suppression of chemotherapy-induced AKT activation. In conclusion, exportin 1 inhibition strongly enhances sensitivity of SCLC tumors to cisplatin and irinotecan, used in first line and second line treatment of SCLC tumors, respectively, and these effects are independent of the SCLC subtype. These results provide preclinical rationale for the combination of selinexor with cisplatin or irinotecan in naïve and relapsed SCLC. The clinical availability of selinexor will allow rapid clinical translation of these results in a disease setting with extremely limited therapeutic options.
Citation Format: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yuan Hao, Andrew Chow, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Umesh K. Bhanot, Juan Qiu, Elisa de Stanchina, Richard P. Koche, Triparna Sen, John T. Poirier, Charles M. Rudin. Exportin 1 inhibition as a therapeutic strategy for small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3594.