Pazopanib, a novel multitargeted kinase inhibitor, shows potent in vitro antitumor activity in gastric cancer cell lines with FGFR2 amplification

Seung Tae Kim, Hye Lim Jang, Su Jin Lee, Jeeyun Lee, Yoon La Choi, Kyoung Mee Kim, Jeonghee Cho, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Masakazu Yashiro, Won Ki Kang, Joon Oh Park

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Pazopanib is an orally bioavailable, ATP-competitive, multitargeted tyrosine kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biologic sequences of pazopanib activities beyond antiangiogenesis are poorly defined. We used a panel of 38 gastric cancer cell lines to test the efficacy of pazopanib. In a growth inhibition assay, genomic changes indicated that pazopanib had differential effects on cell growth. Treatment of the KATO-III, OCUM-2M, SNU-16, and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 to 2.0 μmol/L, whereas the same treatment of those cell lines without FGFR2 amplification had no growth-inhibitory effects. In the ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by FGFR2-expressing NIH 3T3 cells with wild-type (WT) FGFR2 and mutant FGFR2 (S252W). Pazopanib also selectively suppressed constitutive FGFR2 signaling and phosphorylation of downstream effectors. In cell-cycle analysis, FGFR2-amplified cells underwent cell-cycle arrest at the G1-S phase after pazopanib treatment, whereas there were no significant effects on cell-cycle progression in cells without FGFR2 amplification treated with pazopanib. In addition, pazopanib increased a substantial fraction of sub-G1 only in FGFR2-amplified cells. These findings show that the activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in a small subset of gastric cancer patients and that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors.

Original languageEnglish
Pages (from-to)2527-2536
Number of pages10
JournalMolecular Cancer Therapeutics
Volume13
Issue number11
DOIs
StatePublished - 1 Nov 2014

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