Reference Detail

Ref Type Journal Article
PMID (27627808)
Authors Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G
Title Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation.
Journal PloS one
Vol 11
Issue 9
Date 2016
URL
Abstract Text Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling through amplifications, mutations, and gene fusions has been implicated in a broad array of cancers (e.g. liver, gastric, ovarian, endometrial, and bladder). ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR addicted cell lines and tumors. Biochemically, ARQ 087 exhibited IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2α, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions. ARQ 087 is currently being studied in a phase 1/2 clinical trial that includes a sub cohort for intrahepatic cholangiocarcinoma patients with confirmed FGFR2 gene fusions (NCT01752920).

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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
Derazantinib Derazantinib 20 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
Derazantinib ARQ 087 FGFR1 Inhibitor 21 FGFR2 Inhibitor 15 KIT Inhibitor 50 Derazantinib (ARQ 087) is an ATP-competitive multi-kinase inhibitor with activity against Fgfr 1/2, FGFR fusions, Arg, Lck, and Kit, which prevents cell proliferation and angiogenesis (PMID: 27627808).
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
FGFR2 over exp Advanced Solid Tumor sensitive Derazantinib Preclinical - Cell line xenograft Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of transformed cells overexpressing Fgfr2 in culture and in cell line xenograft models (PMID: 27627808). 27627808
FGFR1 fusion hematologic cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of hematologic cancer cells harboring FGFROP2-FGFR1 fusion in culture (PMID: 27627808). 27627808
FGFR1 over exp Advanced Solid Tumor sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of transformed cells overexpressing Fgfr1 in culture (PMID: 27627808). 27627808
FGFR3-TACC3 urinary bladder cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of bladder cancer cell lines harboring FGFR3-TACC3 fusion in culture (PMID: 27627808). 27627808
FGFR3-BAIAP2L1 urinary bladder cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of bladder cancer cells harboring FGFR3-BAIAP2L1 fusion in culture (PMID: 27627808). 27627808
FGFR2 amp breast cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of breast cancer cells harboring FGFR2 amplification in culture (PMID: 27627808). 27627808
FGFR2 S252W endometrial cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of endometrial cancer cells harboring FGFR2 S252W in culture (PMID: 27627808). 27627808
FGFR3-BAIAP2L1 Advanced Solid Tumor sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of transformed cells expressing FGFR3-BAIAP2L1 in culture (PMID: 27627808). 27627808
FGFR2-CASP7 Advanced Solid Tumor sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of transformed cells expressing FGFR2-CASP7 in culture (PMID: 27627808). 27627808
FGFR2 amp FGFR2-COL14A1 colon cancer sensitive Derazantinib Preclinical - Cell line xenograft Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited Fgfr signaling and growth of colon cancer cells harboring FGFR2 amplification and FGFR2-COL14A1 fusion in culture and in cell line xenograft models (PMID: 27627808). 27627808
KIT over exp Advanced Solid Tumor sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of transformed cells overexpressing Kit in culture (PMID: 27627808). 27627808
FGFR2 amp stomach cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited Fgfr signaling and growth of gastric cancer cells harboring FGFR2 amplification in culture (PMID: 27627808). 27627808
FGFR2 N549K endometrial cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of endometrial cancer cell lines harboring FGFR2 N549K in culture (PMID: 27627808). 27627808
FGFR2 amp FGFR2 fusion stomach cancer sensitive Derazantinib Preclinical - Cell line xenograft Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited Fgfr signaling and growth of gastric cancer cells harboring FGFR2 amplification and PDHX-FGFR2 fusion in culture, resulted in tumor regression in cell line xenograft models (PMID: 27627808). 27627808
FGFR3 K652E urinary bladder cancer sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of bladder cancer cells harboring FGFR3 K652E in culture (PMID: 27627808). 27627808
FGFR2 - CIT Advanced Solid Tumor sensitive Derazantinib Preclinical - Cell culture Actionable In a preclinical study, Derazantinib (ARQ 087) inhibited growth of transformed cells expressing FGFR2-CIT in culture (PMID: 27627808). 27627808