4.5 Article

SKI-G-801, an AXL kinase inhibitor, blocks metastasis through inducing anti-tumor immune responses and potentiates anti-PD-1 therapy in mouse cancer models

Journal

CLINICAL & TRANSLATIONAL IMMUNOLOGY
Volume 11, Issue 1, Pages -

Publisher

WILEY
DOI: 10.1002/cti2.1364

Keywords

AXL; immunotherapy; kinase inhibitor; metastasis; small molecule

Categories

Funding

  1. Deawoong Foundation [DF-201911-0000001]
  2. Dongin Sports Research Grant of Yonsei University College of Medicine [6-2019-0128]
  3. Ministry for Health & Welfare Affairs [HI19C0744010020]
  4. National Research Foundation of Korea [2017R1D1A1B0303211014]
  5. Oscotec Inc. [2019-31-0802]

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This study evaluated the anti-tumor and anti-metastatic activities of the AXL small-molecule inhibitor SKI-G-801 alone and in combination with anti-PD-1 therapy. The results showed that SKI-G-801 robustly inhibited pAXL expression and significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. The combination of SKI-G-801 and anti-PD-1 therapy had superior survival benefits by inducing more profound T-cell responses.
Objectives. AXL-mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti-tumor and anti-metastatic activities of SKI-G-801, a small-molecule inhibitor of AXL, alone and in combination with anti-PD-1 therapy. Methods. In vitro pAXL inhibition by SKI-G-801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti-metastatic potential of SKI-G-801. Furthermore, SKIG-801, anti-PD-1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application. Results. SKI-G-801 robustly inhibited pAXL expression in various cell lines. SKI-G-801 alone or in combination with anti-PD-1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI-G-801 inhibited the growth of B16F10 and 4T1 tumor-bearing mice but not immune-deficient mice. An antibody depletion assay revealed that CD8(+) T cells significantly contributed to SKI-G-801-mediated survival. Anti-PD-1 and combination group were observed the increased CD8(+) Ki67(+) and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid-derived suppressor cell (G-MDSC) compared to the control group. The neoadjuvant combination of SKI-G-801 and anti-PD-1 therapy achieved superior survival benefits by inducing more profound T-cell responses in the 4T1 syngeneic mouse model. Conclusion. SKI-G-801 significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. Our results suggest that SKI-G-801 has the potential to overcome anti-PD-1 therapy resistance and allow more patients to benefit from anti-PD-1 therapy.

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