Abstract 3858: Exploring Exportin-1 as a therapeutic vulnerability in squamous cell carcinoma

Abstract

Abstract Introduction: Squamous cell carcinomas (LUSCs) account for 25-30% cases of non-small cell lung cancers, making them the second most common histology of lung cancer after adenocarcinomas. For the latter, molecular characterization has defined tumor subsets with discrete driver alterations sensitive to targeted inhibitors, leading to significant improvement in patient survival. However, for LUSCs, to date no specific drivers have been described that are amenable for pharmacological targeting and no targeted therapies are approved for use in this setting. Despite decades of research, LUSCs are still treated with cytotoxic chemotherapy, and now concomitant immunotherapy, which does not achieve durable responses in most patients. Thus, identification of targetable vulnerabilities in this setting remains a critical unmet clinical need. Preliminary data from our lab has identified the nuclear exporter exportin 1 as a therapeutic vulnerability in small cell lung carcinomas. Exportin 1 (XPO1) inhibition with Selinexor, a drug approved for clinical use in the setting of hematological malignancies, induces significant sensitivity in combination with cisplatin and irinotecan. Here, we explored the role of XPO1 as a therapeutic target in LUSC. Methods: We performed a comprehensive multi-omic molecular characterization of a library of LUSC patient-derived xenografts (PDXs) (N=28, with 17 clinical samples being matched pairs). IHC, RNA-seq and NGS via MSK-IMPACT were performed on 27 samples. To examine the potential of XPO1 inhibition as sensitizer to chemotherapy in LUSC, we performed genetic and pharmacological inhibition experiments in LUSC cell lines exhibiting high XPO1 expression. Results: Of the 28 models, 19 samples (68%) were from primary tumors and 9 samples (32%) from metastasis. The sample set were roughly split in half with regard to treatment status; 15 samples (54%) were treatment naïve and 13 sample were treated (46%).XPO1 is highly expressed in LUSCs clinical specimens compared to other tumor types, and its knockdown reduces tumorigenic features of LUSC cell lines with high XPO1 expression, including proliferation and anchorage-independent growth. Targeted XPO1 inhibition with selinexor induces chemotherapy sensitization to carboplatin and paclitaxel, drugs currently used in the treatment of LUSC, as depicted by high cytotoxic synergy scores of selinexor with either drug. Conclusion: Our data suggest that XPO1 expression may exert pro-oncogenic effects in LUSC, consistent with its upregulation in this tumor setting, and that its inhibition with selinexor may strongly sensitize to chemotherapy. Assessment of efficacy of combination therapies with selinexor in vivo will assess the potential of these combinations as a therapeutic approach for LUSC tumors. The clinical availability of selinexor would allow immediate clinical translation of the results generated in this project. Citation Format: Vidushi Durani, Rebecca Caeser, Charles M. Rudin, Alvaro Quintanal-Villalonga, Harsha Sridhar, Parvathy Manoj, Sam E. Tischfield, Marina Asher, Umeshkumar Bhanot, Jacklynn V. Egger, Nicholas D. Socci D. Socci, Nisargbhai S S. Shah, Elisa de Stanchina, Natasha Rekhtman. Exploring Exportin-1 as a therapeutic vulnerability in squamous cell carcinoma. [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 3858.