VS-4718, a Potent Focal Adhesion Kinase (FAK) Inhibitor, Exhibits Anticancer Activity in Leukemia Models in Vitro and in Vivo

Abstract Current chemotherapy is effective in killing leukemic blasts in the periphery, but not leukemic stem cells (LSCs) in the bone marrow, which are thought to be responsible for the high relapse rate in leukemia. Thus, new therapies that effectively target LSCs are urgently needed to prevent cancer relapse. Accumulating evidence supports an essential role for adhesion pathways: particularly integrin beta 3 and its downstream focal adhesion kinase (FAK) in the maintenance of LSCs (Miller et al., Cancer Cell 2013; Despeaux et al., Stem Cells 2012). Previously, we have shown that FAK inhibitors preferentially target cancer stem cells in solid tumors (Shapiro et al., Sci Transl Med, 2014; Kolev et al., AACR 2013). We are extending our investigation of FAK inhibitors into hematological malignancies and report here that the FAK inhibitor VS-4718 displays anticancer activity in leukemia models both in vitro and in vivo. VS-4718 is a potent and orally bioavailable small molecule compound that targets cancer stem cells through inhibition of FAK kinase which is currently being tested in a Phase 1 clinical trial (NCT01849744). The anti-proliferative effect of VS-4718 was evaluated in a panel of 10 cell lines derived from patients with acute promyelocytic leukemia (APL), T-cell acute lymphocytic leukemia (T-ALL), B-cell acute lymphocytic leukemia (B-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) using a CellTiter-Glo cell viability assay on tissue culture or collagen coated plates. VS-4718 displayed anti-proliferative effects against most of these cell lines, with MV-4-11 AML being the most sensitive with an EC50 value of 200 nM. We further investigated the in vivo efficacy of VS-4718 against AML in both subcutaneous and disseminated models using the MV-4-11 cell line. Nude mice bearing MV-4-11 subcutaneous xenografts were treated orally twice daily with either vehicle control or VS-4718 for 14 days. 75 mg/kg VS-4718 caused 50% tumor growth delay and significantly extended median survival from 28 days to 48 days (p < 0.05). Moreover, tumor regression was observed in 4 out of 10 mice. We extended these observations to a disseminated MV-4-11 AML model to incorporate bone marrow stromal biology. When compared with vehicle control, VS-4718 dosed at 25 or 75 mg/kg, on a twice daily oral dosing schedule for 14 days, resulted in 40% and 76% increase in mouse life span, and significantly extended survival with p values < 0.05 and < 0.001 (log rank test), respectively. The effect of VS-4718 on leukemia stem cells and minimal residual disease (MRD) is currently under investigation. Taken together, results of our preclinical studies suggest that VS-4718 may have activity against leukemia that warrants further investigation. Disclosures Tam: Verastem: Employment. Ring:Verastem: Employment. Trombino:Verastem: Employment. Weaver:Verastem: Employment, Equity Ownership. Pachter:Verastem Inc.: Employment, Equity Ownership. Padval:Verastem: Employment. Xu:Verastem: Employment.