The Novel Selective Pan-TRK Inhibitor ONO-7579 Exhibits Antitumor Efficacy Against Human Gallbladder Cancer In Vitro

Makoto Kawamoto; Keigo Ozono; Yasuhiro Oyama; Akio Yamasaki; Yoshinao Oda; Hideya Onishi

doi:10.21873/anticanres.12435

The Novel Selective Pan-TRK Inhibitor ONO-7579 Exhibits Antitumor Efficacy Against Human Gallbladder Cancer In Vitro

Anticancer Res. 2018 Apr;38(4):1979-1986. doi: 10.21873/anticanres.12435.

Authors

Makoto Kawamoto^{1

2}, Keigo Ozono³, Yasuhiro Oyama^{1

2}, Akio Yamasaki^{1

2}, Yoshinao Oda³, Hideya Onishi⁴

Affiliations

¹ Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁴ Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ohnishi@surg1.med.kyushu-u.ac.jp.

PMID: 29599313
DOI: 10.21873/anticanres.12435

Abstract

We previously reported that brain-derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase 2 (NTRK2/TRKB) signaling contributes to induction of malignant phenotype of gallbladder cancer (GBC). Recently, pan-TRK inhibitors have been evaluated and their dramatic clinical activity is being shown for a variety of cancer types harboring an NTRK rearrangement in phase I trials. ONO-7579 is an oral pan-TRK inhibitor currently under investigation in phase I/II clinical trial for TRK-rearranged solid tumors. In this study, we evaluated the anticancer effect of ONO-7579 using GBC cells with or without KRAS mutant, NOZ, TYGBK-1. Our study showed that ONO-7579 had a suppressive effect on GBC proliferation in TYGBK-1, and on invasive potential and vascular endothelial growth factor expression in TYGBK-1 and NOZ. Our data indicated that ONO-7579 could be a promising treatment option for patients with GBC.

Keywords: ONO-7579; TRK inhibitor; TRKB; gallbladder cancer.

MeSH terms

Brain-Derived Neurotrophic Factor / antagonists & inhibitors
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Epithelial-Mesenchymal Transition / drug effects
Gallbladder Neoplasms / drug therapy*
Gallbladder Neoplasms / enzymology
Gallbladder Neoplasms / metabolism
Gallbladder Neoplasms / pathology
Humans
Membrane Glycoproteins / antagonists & inhibitors*
Membrane Glycoproteins / biosynthesis
Neoplasm Invasiveness
Organic Chemicals / chemistry
Organic Chemicals / pharmacology*
Protein Kinase Inhibitors / pharmacology*
Receptor, trkB / antagonists & inhibitors*
Receptor, trkB / biosynthesis
Vascular Endothelial Growth Factor A / biosynthesis

Substances

Brain-Derived Neurotrophic Factor
Membrane Glycoproteins
ONO-7579
Organic Chemicals
Protein Kinase Inhibitors
VEGFA protein, human
Vascular Endothelial Growth Factor A
BDNF protein, human
Receptor, trkB
tropomyosin-related kinase-B, human