Abstract 4196: Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model

Abstract

Abstract Aberrant expression of TAM family receptor tyrosine kinases, comprising Tyro3, Axl and Mer, is found in virtually every type of human cancer. The expression levels correlate positively with disease staging and prognostic outcome, attributing to metastasis and drug resistance. The TAM kinases have recently emerged as a dual oncological therapeutic target, owing to their immunosuppressive activity. Apart from targeting tumor-survival/growth pathways their inhibition also unleash the anti-tumor immunity in the tumor microenvironment. In our efforts to develop small-molecule inhibitors targeting the TAM kinases, we identified SLC-391 as one of the most promising preclinical candidates with potent activity towards both Axl and Mer, which play roles in maintaining tumor survival and immunosuppressive tumor microenvironment, respectively. Pharmacodynamic studies of SLC-391 in CT26 syngeneic mouse model revealed increase in the number of NK cells and the ratio of M1/M2-polarized macrophages in the treatment group relative to the vehicle control, followed by the rise of CD8+ T/Treg ratio and reduction in immunosuppressive myeloid cells. This is indicative of sequential engagement and stimulation of pro-inflammatory innate immune response and adaptive immune response. In addition, a synergistic anti-tumor effect was observed when the anti-PD-1 insensitive CT-26 model was treated with a combination of SLC-391 and an anti-PD-1 antibody, suggesting that blocking the Axl/Mer-mediated immunosuppressive pathway may significantly enhance the therapeutic efficacy of immune checkpoint inhibitors. In summary, the anti-tumor activity of SLC-391 is mediated by directly inhibiting tumor cell growth as well as reversing the immunosuppressive tumor microenvironment. Citation Format: Shenshen Lai, Hong Zhang, Jun Yan, Zaihui Zhang. Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2017-4196