Reference Detail

Ref Type

Journal Article

PMID

(31438996)

Authors

Peng X, Hou P, Chen Y, Dai Y, Ji Y, Shen Y, Su Y, Liu B, Wang Y, Sun D, Jiang Y, Zha C, Xie Z, Ding J, Geng M, Ai J

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of experimental & clinical cancer research : CR	38	1	2019 Aug 22	372	J Exp Clin Cancer Res

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
3D185	3D185	9	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
3D185		3D-185\|3D 185\|HH185	CSF1R Inhibitor 28 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19	3D185 inhibits FGFR1/2/3 and CSF-1R, which potentially inhibits Fgfr signaling, modulates the tumor microenvironment, and inhibits tumor growth (PMID: 31438996).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	lung cancer	sensitive	3D185	Preclinical - Cell line xenograft	Actionable	In a preclinical study, 3D185 inhibited downstream signaling and proliferation of a lung cancer cell line harboring FGFR1 amplification in culture and inhibited signaling and induced dose-dependent tumor growth inhibition in a cell line xenograft model (PMID: 31438996).	31438996
FGFR2 amp	stomach cancer	sensitive	3D185	Preclinical - Cell line xenograft	Actionable	In a preclinical study, 3D185 inhibited downstream signaling and proliferation of gastric cancer cell lines harboring FGFR2 amplification in culture and induced dose-dependent tumor growth inhibition in a cell line xenograft model (PMID: 31438996).	31438996
FGFR2 amp	colorectal cancer	sensitive	3D185	Preclinical - Cell culture	Actionable	In a preclinical study, 3D185 inhibited proliferation of a colorectal cancer cell line harboring FGFR2 amplification in culture (PMID: 31438996).	31438996
FGFR3 fusion FGFR3 mut	multiple myeloma	sensitive	3D185	Preclinical - Cell culture	Actionable	In a preclinical study, 3D185 inhibited proliferation of a multiple myeloma cell line harboring an FGFR3 fusion and an FGFR3 mutation in culture (PMID: 31438996).	31438996
FGFR1 V561M	Advanced Solid Tumor	predicted - sensitive	3D185	Preclinical - Biochemical	Actionable	In a preclinical study, 3D185 inhibited kinase activity of FGFR1 V561M in an in vitro assay (PMID: 31438996).	31438996
FGFR2 amp	triple-receptor negative breast cancer	sensitive	3D185	Preclinical - Cell culture	Actionable	In a preclinical study, 3D185 inhibited proliferation of a triple-negative breast cancer cell line harboring FGFR2 amplification in culture (PMID: 31438996).	31438996
FGFR3 S249C	urinary bladder cancer	sensitive	3D185	Preclinical - Cell culture	Actionable	In a preclinical study, 3D185 inhibited downstream signaling and proliferation in a bladder cancer cell line harboring FGFR3 S249C in culture (PMID: 31438996).	31438996
FGFR3 amp	urinary bladder cancer	sensitive	3D185	Preclinical - Cell culture	Actionable	In a preclinical study, 3D185 inhibited proliferation of a bladder cancer cell line harboring FGFR3 amplification in culture (PMID: 31438996).	31438996
FGFR2 N549H	Advanced Solid Tumor	predicted - sensitive	3D185	Preclinical - Biochemical	Actionable	In a preclinical study, 3D185 inhibited the kinase activity of FGFR2 N549H in an in vitro assay (PMID: 31438996).	31438996