Abstract 6915: Cytoplasmic complex of SLK-XPO7: A targetable player in extrahepatic cholangiocarcinoma

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Abstract Cholangiocarcinoma (CCA) is a highly aggressive malignancy that arises from the biliary tree, and often presents with advanced stage disease. For patients with disease arising from intrahepatic bile ducts, genomic analyses have revealed targetable mutations. Unfortunately, these mutations are exceedingly rare in extrahepatic disease (eCCA), limiting therapeutic options. It is therefore necessary to investigate the functional crosstalk resulting from different signal transduction pathways to identify new treatment options for this patient population. IHC analysis of eCCA tumors from 170 patients demonstrated intense Exportin-7 (XPO7) cytoplasmic staining in 30% of the samples, which correlated with abbreviated survival. With the co-immunoprecipitation, proteomic analysis and molecular docking, we demonstrated that XPO7 exists in a molecular complex with the Ste-20 like kinase (SLK) and beta-tubulin in the cytoplasm. A kinome screen identified tivozanib, a potent VEGFR2 inhibitor, as a moderate inhibitor of SLK kinase (IC50 - 36 nM @ 10 µM ATP or 2.2 µM @ 1 mM ATP) and cellular target engagement (NanoBRET) of 884 nM. The X-ray crystallography results confirmed that tivozanib binds to the SLK ATP-binding pocket, with the DGF motif in the inactive “DGF-out” conformation in the N-terminal region. In in vitro experiments, shRNA-mediated knockdown of SLK and tivozanib treatment in cholangiocarcinoma cell lines showed reduced spheroid forming capacity with downregulation of PI3K-AKT-mTOR pathway. This resulted in reduction in expression of phosphorylated mTOR (S2448), AKT (T308), and S6 (S235/236). SLK KD and tivozanib treatment also resulted in upregulation of ATM-dependent DNA damage pathway in cholangiocarcinoma cell lines with resulting downregulation of beta-tubulin and G2/M cell cycle arrest confirming its potential role in impacting the cellular processes. Moreover, tivozanib regressed tumors in established eCCA patient derived xenografts with cytoplasmic XPO7 expression. We further confirmed our results in our ex vivo system by treating eCCA patient tumor slice cultures with tivozanib. The IHC and Western blotting results confirmed the significant reduction of PI3K-AKT-mTOR pathway in high XPO7/SLK-expressing tumors (N=3) compared to the lower expression pattern (N=7). Lastly, tivozanib monotherapy demonstrated in vivo efficacy in the patients with high XPO7 expression with tumor regression and arrest of tumor progression (RECIST) in an ongoing clinical trial (NCT04645160). Citation Format: Priyanka Prakash Desai, Surajit Sinha, Emily Smith, Reed I. Ayabe, Pedro Torres-Ayuso, Ashley Rainey, Himanshu Verma, Kirsten Remmert, Tracey Pu, Craig Thomas, John Brognard, William J. Moore, Gregory Tawa, Thorkell Andresson, David Kleiner, Michael B. Yaffe, Jonathan M. Hernandez. Cytoplasmic complex of SLK-XPO7: A targetable player in extrahepatic cholangiocarcinoma [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 6915.

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