22P - Exploring exportin-1 as a therapeutic vulnerability in lung squamous cell carcinoma

Background

Squamous cell carcinomas (LUSCs) are the second most common histology of lung cancer after adenocarcinomas. 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. Preliminary data from our lab has identified the nuclear exporter Exportin 1 (XPO1) as a therapeutic vulnerability in small-cell lung carcinomas. XPO1 inhibition with selinexor, induces significant sensitivity in combination with chemotherapy in different tumor types. Here, we explored the role of XPO1 as a therapeutic target in LUSC.

Methods

We performed a comprehensive histological and proteogenomic (Immunohistochemistry, MSK-IMPACT, Methylation array, RNAseq, and DIA- Mass spec characterization of a library of LUSC patient-derived xenografts (PDXs) (N=28) and matched clinical specimens (N=17)). To examine the potential of XPO1 inhibition as a therapeutic target in LUSC, we performed genetic and pharmacological inhibition experiments in LUSC cell lines and PDXs.

Results

Genomic characterization of our LUSC PDX platform identified frequent XPO1 gene gains and amplifications. This observation was confirmed in the TCGA LUSC dataset with a 10.7% frequency for XPO1 amplification, which correlated with high XPO1 mRNA expression. IHC assessment of XPO1 expression in the PDXs and an independent cohort of LUSC clinical specimens revealed high exportin 1 expression in these tumors. XPO1 knockdown reduced the tumorigenic potential of LUSC cell lines, including proliferation and anchorage-independent growth. Targeted XPO1 inhibition with selinexor was synergistic with the chemotherapeutic agent irinotecan in vitro. Selinexor showed exquisite efficacy in an array of LUSC PDXs as monotherapy and strongly sensitized these to irinotecan.

Conclusions

Our data suggest that XPO1 may exert a pro-oncogenic role in LUSC and that its inhibition may represent a promising therapeutic approach for LUSC tumors, both as monotherapy or in combination with irinotecan. The clinical availability of selinexor will allow immediate clinical translation of the results generated in this project in a setting where no targeted therapies are available.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

V. Durani.

Funding

Druckenmiller Center for Cancer Research funding.

Disclosure

Á. Quintanal-Villalonga: Financial Interests, Personal, Other, Received Honoraria from AZ: AstraZeneca. C.M. Rudin: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, Syros, Auron, Bridge Medicines, DISCO, Earli, Harpoon Therapeutics. All other authors have declared no conflicts of interest.