Abstract 4403: Preclinical evaluation of LY2801653, an orally bioavailable small molecule oncokinase inhibitor, in cholangiocarcinoma models
Authors: Yan Sau-Chi Betty , Um Suzane L. , Peek Victoria L. , Thobe Megan N. , Credille Kelly M. , Stephens Jennifer R. , Manro Jason R. , Ballard Darryl W. , Baker Jessica A. , Cook Joel D. , Konicek Bruce W. , Graff Jeremy R. , Holzer Timothy R. , Walgren Richard A. 
Published: May 2015

Abstract
Cholangiocarcinoma (CCA) is an aggressive and locally invasive biliary tract malignancy with a poor prognosis and no approved drug treatment. LY2801653 is an orally bioavailable small molecule oncokinase inhibitor1 of MET, a receptor reported to be dysregulated and correlated with a poor outcome in CCA. We evaluated additional oncotargets of LY2801653 (MET/HGF, pMET, AXL/pAXL, the MKNK1/2 substrate p-eIF4E, and ROS1) in 7 CCA cell lines (EGI-1, TFK-1, SNU245, SNU478, SNU869, SNU1079, and SNU1196) and 5 CCA patient-derived mouse xenograft (PDX) tumors. Cell line expression of MET, EGFR and p-eIF4E were evaluated by western blot. Although HGF expression was not detected in any of the cell lines by ELISA, pMET was detected in 5 cell lines (not in TFK-1 or SNU1079). ROS1 fusion was not detected in the 7 cell lines using break-apart FISH probes. Very high AXL and pAXL were detected in the SNU1196 line by western blot. Despite the high levels of pAXL, further increases in pAXL were noted after addition of its ligand, Gas6. In the SNU1196 cell line, pAXL expression and cell proliferation were completely inhibited by LY2801653, but not by a MET-specific inhibitor PF4217903. HGF-induced SNU1196 cell migration was inhibited equally well by LY2801653 and PF4217903. Unlike CCA cell line derived mouse xenograft tumors, the 5 PDX tumors retained prominent desmoplastic stroma. As analyzed by immunohistochemistry (IHC), MET was highly expressed in 3 of the 5 PDX tumors, and high levels of p-eIF4E were expressed in all 5. Increased AXL expression (IHC) appeared to be associated with more poorly differentiated PDX tumors.
LY2801653 demonstrated potent in vivo anti-tumor activity in several CCA xenograft models. In a xenograft mouse model with the extrahepatic CCA derived EGI-1 cell line, treatment with LY2801653 at 24 mg/kg dosed twice daily resulted anti-tumor effect of 38.5% (% treated/control). In the SNU869 extrahepatic CCA cell line-derived xenograft mouse model, combination treatment with LY2801653 (12 mg/kg twice daily) and either cisplatin (5 mg/kg once weekly) or gemcitabine (60 mg/kg once weekly) resulted in an additive anti-tumor effect as compared to LY2801653 alone. Moreover, the combination of LY2801653 with gemcitabine resulted in tumor regression in this model. In vivo studies are ongoing with LY2801653 in the extrahepatic SNU1196 CCA cell line-derived xenograft model as well as two of the PDX models. The preclinical data in this study support the ongoing phase 1 clinical evaluation of LY2801653 in cholangiocarcinoma patients (trial I3O-MC-JSBA, NCT01285037). (1 - Yan et al. Invest New Drugs 2013;31:833-44).
Citation Format: Sau-Chi Betty Yan, Suzane L. Um, Victoria L. Peek, Megan N. Thobe, Kelly M. Credille, Jennifer R. Stephens, Jason R. Manro, Darryl W. Ballard, Jessica A. Baker, Joel D. Cook, Bruce W. Konicek, Jeremy R. Graff, Timothy R. Holzer, Richard A. Walgren. Preclinical evaluation of LY2801653, an orally bioavailable small molecule oncokinase inhibitor, in cholangiocarcinoma models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4403. doi:10.1158/1538-7445.AM2014-4403