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

Abstract

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.

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

“…In vivo pharmacologic inhibiting pan-TAM Tyrosine Kinases, TYRO3, AXL, and MERTK, diminishes MDSC suppressive capability, promotes CD8 + T cell infiltration, slows tumor growth, and augments anti-PD-1 immunotherapy [ 247 – 249 ]. Consistently, another AXL kinase inhibitor, SKI-G-801, blocks metastasis through inducing anti-tumor immune responses and potentiates anti-PD-1 therapy in multiple mouse cancer models (including B16F10 melanoma, CT26 colon, 4T1 breast, TC1 and C3PQ lung cancer models) [ 250 , 251 ]. Similarly, combining AXL kinase inhibitor R428 with anti–PD-1 in a mouse HER2 + breast cancer model reduces the primary tumor and metastatic burdens [ 171 ].…”

“… [ 294 ] Lung cancers Sensitized mesenchymal lung cancer cells to CTLs and NK cells via intracellular adhesion molecule-1 (ICAM-1)/leukocyte function-associated antigen-1 (ICAM1/LFA-1) and UL16 binding protein 1 (ULBP1)/ natural killer group 2, member D (NKG2D) interactions. [ 246 ] BMS-777607 Murine Model of Triple-Negative Breast Cancer Blocks macrophage efferocytosis and Gas6-PS–opsonized apoptotic cell, and enhances anti-PD-1 mAb efficacy via up-regulating PD-L1 expression [ 249 ] SKI-G-801 B16F10 melanoma, CT26 colon and 4T1 breast model Blocks metastasis through inducing CD8 + T cells, decreasing M2 macrophage and potentiates anti-PD-1 therapy [ 250 ] TC1 and C3PQ mouse tumor models Improves efficiency of anti-PD-1 therapy, exhibiting increased proportion of effector memory helper T cells, CD86+ macrophages. [ 251 ] Enapotamab vedotin (EnaV) Melanoma and lung cancer models Induced ICB benefit and promoted the induction of a memory-like phenotype in cytotoxic T cells.…”

“…and Gas6-PS-opsonized apoptotic cell, and enhances anti-PD-1 mAb efficacy via up-regulating PD-L1 expression[249] SKI-G-801 B16F10 melanoma, CT26 colon and 4T1 breast model Blocks metastasis through inducing CD8 + T cells, decreasing M2 macrophage and potentiates anti-PD-1 therapy[250] …”

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

“…In syngeneic murine glioblastoma models, targeting AXL plus PD-1 effectively prolonged the survival of glioblastoma-bearing mice ( 183 ). A recent study has reported similar results using a new selective AXL/FLT3 inhibitor, SKI-G-801 in B16F10 melanoma, CT26 colon, and 4T1 BCa models ( 185 ). The results highlight the potential of AXL targeting to overcome anti-PD-1 therapy resistance.…”

Phase 1b study of batiraxcept in combination with durvalumab in patients with platinum-resistant ovarian cancer

“… 17 Therefore, AXL inhibition and ICI may synergize to create improved anti-tumor immune responses, and this has been demonstrated with anti-PD-1 therapy in pre-clinical tumor models. 18 Clinically, in patients with melanoma, AXL transcript levels were significantly correlated with resistance to anti-PD-1 checkpoint therapy, 19 , 20 highlighting the importance of investigating AXL inhibitors in the clinic with the goal of increasing ICI efficacy.…”