309 (PB089) - AB801 is a potent and selective AXL inhibitor that demonstrates significant anti-tumor activity in combination with standard of care therapeutics

Abstract

Background: The receptor tyrosine kinase AXL, expressed in cancer, stromal, and select immune cells, has been implicated in resistance to chemotherapy, targeted therapies & immunotherapies. AXL expression correlates with poor prognosis in cancer patients. Activation of AXL can occur in a ligand-dependent manner via its ligand, growth arrest specific protein 6 (Gas6), or in a ligand-independent manner, both of which facilitate AXL phosphorylation & initiation of signaling cascades promoting cancer cell proliferation, survival, and an immunosuppressive microenvironment. Here we present the preclinical evaluation of a novel, highly potent, and selective AXL inhibitor, AB801. Materials and Methods: Inhibition of AXL phosphorylation in cancer cells was evaluated by Western blot and levels of soluble and cell-surface AXL were assessed by ELISA and flow cytometry, respectively. Downstream signaling of AXL was evaluated by Western blot and qPCR. Pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor efficacy in combination with standard of care therapies were evaluated in murine cancer models. Results: AB801 inhibits both ligand-dependent and ligand-independent AXL phosphorylation. AXL phosphorylation and subsequent signaling leads to receptor internalization, thereby decreasing both surface AXL and soluble AXL levels. AB801 inhibits AXL activity in a concentration-dependent manner reducing AXL phosphorylation and increasing both surface AXL expression and soluble AXL levels. Moreover, AXL inhibition results in upregulation of cell surface proteins that mediate immune/cancer cell interaction, e.g., LFA-1. Significant anti-tumor efficacy is observed in combination with targeted therapies in several in vivo models. Importantly, AB801 treatment significantly reduces tumor growth after relapse to single-agent therapy. Conclusions: AB801 demonstrates significant anti-tumor activity in combination with standard of care therapeutics. Selective AXL inhibition is a promising therapeutic strategy to overcome resistance to therapy. Conflict of interest: Ownership: Arcus Biosciences Shareholder Corporate-sponsored Research: Employee of Arcus Biosciences.