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

Pazopanib is an orally bioavailable, ATP-competitive, multi-targeted kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biological sequences of pazopanib activities beyond anti-angiogenesis are poorly defined. We used a panel of 38 GC cell lines in order 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 GC cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 - 2.0 microM, while 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 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 GC patients and that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors.

http://mct.aacrjournals.org/content/early/2014/09/23/1535-7163.MCT-14-0255.abstract

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