Sulfatinib, a novel multi-targeted tyrosine kinase inhibitor of FGFR1, CSF1R, and VEGFR1-3, suppresses osteosarcoma proliferation and invasion via dual role in tumor cells and tumor microenvironment

Song Liao; Jianxiong Li; Song Gao; Yuchen Han; Xinli Han; Yanan Wu; Jingyou Bi; Meng Xu; Wenzhi Bi

doi:10.3389/fonc.2023.1158857

Sulfatinib, a novel multi-targeted tyrosine kinase inhibitor of FGFR1, CSF1R, and VEGFR1-3, suppresses osteosarcoma proliferation and invasion via dual role in tumor cells and tumor microenvironment

Front Oncol. 2023 Jun 8:13:1158857. doi: 10.3389/fonc.2023.1158857. eCollection 2023.

Authors

Song Liao^{1

2}, Jianxiong Li^{1

2}, Song Gao², Yuchen Han^{1

2}, Xinli Han², Yanan Wu^{1

2}, Jingyou Bi^{1

2}, Meng Xu², Wenzhi Bi²

Affiliations

¹ Medical School of Chinese PLA, Beijing, China.
² Senior Department of Orthopedics, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, China.

Abstract

Introduction: Tumor progression is driven by intrinsic malignant behaviors caused by gene mutation or epigenetic modulation, as well as crosstalk with the components in the tumor microenvironment (TME). Considering the current understanding of the tumor microenvironment, targeting the immunomodulatory stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) could provide a potential therapeutic strategy. Here, we investigated the effect of sulfatinib, a multi-targeted tyrosine kinase inhibitor (TKI) of FGFR1, CSF1R, and VEGFR1-3, on the treatment of osteosarcoma (OS).

Methods: In vitro, the antitumor effect was tested by clony formation assay and apoptosis assay.The inhibition of tumor migration and invasion was detected by Transwell assay, and the de-polarization of macrophage was detected by flow cytometry.In vivo, subcutaneous and orthotopic tumor models were established to verify antitumor effect, and the underlying mechanism was verified by immunohistochemistry(IHC), immunofluorescence(IF) and flow cytometry.

Results: Sulfatinib suppressed OS cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) by blocking the secretion of basic fibroblast growth factor (bFGF) in an autocrine manner. In addition, it regulated immune TME via inhibition of the migration of skeletal stem cells (SSCs) to the TME and the differentiation from SSCs to CAFs. Moreover, sulfatinib can suppress OS by modulation of the TME by inhibiting M2 polarization of macrophages. Systemic treatment of sulfatinib can reduce immunosuppression cells M2-TAMs, Tregs, and myeloid-derived suppressor cells (MDSCs) and increase cytotoxic T-cell infiltration in tumors, the lungs, and the spleens.

Discussion: Our preclinical experiments have shown that sulfatinib can inhibit the proliferation, migration, and invasion of OS by playing a dual role on tumor cells and the tumor microenvironment simultaneously and systematically reverse immunosuppression to immune activation status, which could be translated into clinical trials.

Keywords: cancer-associated fibroblast; osteosarcoma; sulfatinib; targeted therapy; tumor microenvironment; tumor-associated macrophage.