Abstract LB462: SLK inhibition results in a DNA damage response in XPO7 overexpressing cholangiocarcinoma

Abstract Cholangiocarcinoma (CCA) is a rare, aggressive cancer that originates from the biliary epithelium. Patients often present with metastatic disease, and 5-year survival rates remain <10% despite recent advances in targeted molecular therapies. In an effort to expand therapeutic options to more patients with this disease, we investigated functional crosstalk through the lens of extracellular vesicles, which revealed Exportin-7 (XPO7) as a highly expressed protein. IHC analysis of 170 patients with CCA demonstrated overexpression of XPO7 in 30% of the samples, which correlated with abbreviated survival. To understand the role of XPO7 in CCA, we carried out co-immunoprecipitation, proteomic analysis and protein modeling. We demonstrated that XPO7 exists in a molecular complex with the Ste-20 like kinase (SLK), with interruption of either protein resulting in decreased tumor xenograft formation. In order to identify potential pharmacologic inhibitors, a kinome screen was run for agents with activity against SLK. We identified tivozanib, a potent VEGFR2 tyrosine kinase inhibitor, as having substantial activity against the serine/threonine kinase activity of SLK, and used x-ray crystallography to confirm ATP-binding pocket with “DGF-out” conformation. Importantly, tivozanib regressed tumors in established CCA patient-derived xenografts overexpressing XPO7, which we confirmed in human tumors using our ex vivo tumor slice culture system. In vitro experiments with both shRNA-mediated knockdown of SLK and tivozanib treatment demonstrated a reduction in PLK1 activation (pT210), with subsequent DNA damage response characterized by upregulation of phospho-DNAPKc (S2056), phospho-H2AX S139, and p27 with decreased signaling through the mTORC1 pathway (p-mTORS2448 and p-RPS6 S235/236). These results were confirmed in human tumors (n=11) using mass spectrometry, IHC and Western blotting. Lastly, tivozanib monotherapy demonstrated in vivo efficacy by RECIST criteria in patients with XPO7 over-expressing CCA (NCT04645160). On treatment biopsies in a responding patient confirmed marked upregulation of p-H2AX S139 with decreased expression of Ki67, p-mTORS2448, p-RPS6 S235/236. Overall these results implicate SLK as a promising target in patients with XPO7-overexpressing CCA. Citation Format: Priyanka Prakash Desai. SLK inhibition results in a DNA damage response in XPO7 overexpressing cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB462.