Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models

doi:10.1186/s13046-019-1357-y

	Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models
	Peng, Xia 1,3; Hou, Pengcong 1,3; Chen, Yi 1,3; Dai, Yang 1,3; Ji, Yinchun 1,3; Shen, Yanyan 1,3; Su, Yi 1,3; Liu, Bo 1,3; Wang, Yueliang 1,3; Sun, Deqiao 1,3
刊名	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
	2019-08-22
卷号	38 期号:1 页码:16
关键词	Kinase inhibitor FGFR CSF-1R Tumor microenvironment
DOI	10.1186/s13046-019-1357-y
通讯作者	Geng, Meiyu(mygeng@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn)
英文摘要	Background The interaction between tumor cells and their immunosuppressive microenvironment promotes tumor progression and drug resistance. Thus, simultaneously targeting tumor cells and stromal cells is expected to have synergistic antitumor effects. Herein, we present for the first time a preclinical antitumor investigation of 3D185, a novel dual inhibitor targeting FGFRs, which are oncogenic drivers, and CSF-1R, which is the major survival factor for protumor macrophages. Methods The antitumor characteristics of 3D185 were assessed by a range of assays, including kinase profiling, cell viability, cell migration, immunoblotting, CD8(+) T cell suppression, and in vivo antitumor efficacy, followed by flow cytometric and immunohistochemical analyses of tumor-infiltrating immune cells and endothelial cells in nude mice and immune-competent mice. Results 3D185 significantly inhibited the kinase activity of FGFR1/2/3 and CSF-1R, with equal potency and high selectivity over other kinases. 3D185 suppressed FGFR signaling and tumor cell growth in FGFR-driven models both in vitro and in vivo. In addition, 3D185 could inhibit the survival and M2-like polarization of macrophages, reversing the immunosuppressive effect of macrophages on CD8(+) T cells as well as CSF1-differentiated macrophage induced-FGFR3-aberrant cancer cell migration. Furthermore, 3D185 inhibited tumor growth via remodeling the tumor microenvironment in TAM-dominated tumor models. Conclusions 3D185 is a promising antitumor candidate drug that simultaneously targets tumor cells and their immunosuppressive microenvironment and has therapeutic potential due to synergistic effects. Our study provides a solid foundation for the investigation of 3D185 in cancer patients, particularly in patients with aberrant FGFR and abundant macrophages, who respond poorly to classic pan-FGFRi treatment.
资助项目	Personalized Medicines - Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020000] ; Personalized Medicines - Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020103] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Natural Science Foundation of China[81773762] ; Natural Science Foundation of China[81473243] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-013]
WOS关键词	TUMOR-ASSOCIATED MACROPHAGES ; FACTOR RECEPTOR INHIBITORS ; TARGETING FGFR ; SELECTIVE INHIBITOR ; MYELOID CELLS ; LUNG-CANCER ; GROWTH ; ANGIOGENESIS ; THERAPY ; FAMILY
WOS研究方向	Oncology
语种	英语
出版者	BMC
WOS记录号	WOS:000483021100005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288811]
专题	中国科学院上海药物研究所
通讯作者	Geng, Meiyu; Ai, Jing
作者单位	1.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Shanghai HaiHe Pharmaceut Co Ltd, 421 Newton Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Peng, Xia,Hou, Pengcong,Chen, Yi,et al. Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models[J]. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2019,38(1):16.
APA	Peng, Xia.,Hou, Pengcong.,Chen, Yi.,Dai, Yang.,Ji, Yinchun.,...&Ai, Jing.(2019).Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,38(1),16.
MLA	Peng, Xia,et al."Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 38.1(2019):16.