Abstract 2197: The AXL kinase inhibitor, TP-0903, demonstrates efficacy in preclinical models of colorectal cancer independent of KRAS mutation status
Authors: Ryan Mangelson, Peter Peterson, Jason M. Foulks, Yuta Matsumura, Lars Mouritsen, Clifford J. Whatcott, David J. Bearss, Steven L. Warner
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the US (2017). Most patients present with stage II or III disease at diagnosis, with the 5-year survival rate between 53-89%. Survival in patients with stage IV CRC, however, is a discouraging 11%. Metastasis in CRC is linked to a mesenchymal phenotype, which is associated with chemoresistance. AXL, a receptor tyrosine kinase, promotes the mesenchymal phenotype in cancer cells and its expression is associated with drug resistance and poor outcomes. TP-0903, a clinical-stage, investigational small molecule inhibitor of AXL has been shown to reverse the mesenchymal phenotype and restore drug sensitivity in cells that no longer respond to standard agents in preclinical models. TP-0903 is hypothesized to be an active agent in CRC through reversal of the mesenchymal phenotype. In cell viability assays of CRC lines, TP-0903 treatment resulted in IC50 values ranging from 4.5 – 123 nM. Notably, cell growth inhibition by TP-0903 was independent of KRAS mutation status; the KRAS mutant HCT-116 line was the most sensitive CRC cell line tested. Mesenchymal markers, including Snail, were suppressed by 7.6-fold (mRNA) and 4.9-fold (protein) in the HCT-116 line at 500 nM. TP-0903 activity was also assessed in vivo using two KRAS mutant CRC models: HCT-116 and a patient-derived xenograft (PDX) model. In the HCT-116 xenograft model, single agent TP-0903 treatment achieved 69% tumor growth inhibition (%TGI) with an oral dosing schedule at 40 mg/kg. In a KRAS-mutant PDX model, TP-0903 achieved 44% TGI when mice were dosed at 40 mg/kg. Pharmacodynamic analyses were performed on tissues from the HCT-116 and PDX models. The ligand for AXL, GAS6, was significantly upregulated in tissues after TP-0903 treatment in both CRC in vivo models while soluble AXL and GAS6 were significantly downregulated in plasma in the PDX model. Furthermore, Axin2, a Wnt/β-catenin regulated gene, was downregulated by TP-0903 in tumor tissue from the PDX model, suggesting inhibition of the Wnt/βcatenin pathway. These data support a potential role for AXL in the promotion of the mesenchymal phenotype in CRC, and showed that AXL inhibition by TP-0903 suppressed the mesenchymal phenotype and was effective against CRC cells regardless of KRAS mutation status. These observations support further clinical investigation of TP-0903 as a potential therapeutic agent in metastatic CRC. A Phase I trial with this investigational agent is ongoing, including patients with KRAS mutant CRC (clincaltrials.gov, NCT02729298). Citation Format: Ryan Mangelson, Peter Peterson, Jason M. Foulks, Yuta Matsumura, Lars Mouritsen, Clifford J. Whatcott, David J. Bearss, Steven L. Warner. The AXL kinase inhibitor, TP-0903, demonstrates efficacy in preclinical models of colorectal cancer independent of KRAS mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2197.