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	Vol	Issue	Date	Pages	Journal Short Title
PloS one	11	9	2016	e0162594	PLoS One

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	15	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Derazantinib		ARQ 087	FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 KIT Inhibitor 57 LCK Inhibitor 6	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).

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
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
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
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
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
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
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 fusion FGFR2 amp	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
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 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
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