Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

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 Journal of experimental & clinical cancer research : CR
Vol 38
Issue 1
Date 2019 Aug 22
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
3D185 3D-185|3D 185|HH185 CSF1R Inhibitor 27 FGFR1 Inhibitor 25 FGFR2 Inhibitor 19 FGFR3 Inhibitor 15 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 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
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
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 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
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
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
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