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

Chun Bong Synn, Sung Eun Kim, Hee Kyu Lee, Min Hwan Kim, Jae Hwan Kim, Ji Min Lee, Ha Ni Jo, Wongeun Lee, Dong Kwon Kim, Youngseon Byeon, Young Seob Kim, Mi Ran Yun, Chae Won Park, Jiyeon Yun, Sangbin Lim, Seong Gu Heo, San Duk Yang, Eun Ji Lee, Seul Lee, Hunmi ChoiYou Won Lee, Jae Seok Cho, Do Hee Kim, Sungho Park, Jung Ho Kim, Yewon Choi, Sung Sook Lee, Beung Chul Ahn, Chang Gon Kim, Sun Min Lim, Min Hee Hong, Hye Ryun Kim, Kyoung Ho Pyo, Byoung Chul Cho

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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, SKI-G-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.

Original languageEnglish
Article numbere1364
JournalClinical and Translational Immunology
Issue number1
Publication statusPublished - 2022

Bibliographical note

Funding Information:
We acknowledge the members of the animal facility and the technicians for their technical assistance. This study was supported by the Deawoong Foundation (DF‐201911‐0000001), Dongin Sports Research Grant of Yonsei University College of Medicine (6‐2019‐0128), Ministry for Health & Welfare Affairs (HI19C0744010020), National Research Foundation of Korea (2017R1D1A1B0303211014) and Oscotec Inc. (2019‐31‐0802).

Publisher Copyright:
© 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc

All Science Journal Classification (ASJC) codes

  • Nursing(all)
  • Immunology and Allergy
  • Immunology


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