PAZOPANIB, A NOVEL MULTI-TARGETED KINASE INHIBITOR, SHOWS POTENT IN VITRO ANTITUMOR ACTIVITY IN GASTRIC CANCER CELL LINES WITH FGFR2 AMPLIFICATION

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Abstract

Background

Pazopanib is an orally bioavailable, ATP-competitive, multi-targeted kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, which results in selective inhibition of VEGF-induced angiogenesis. However, the biological sequences of pazopanib activities beyond anti-angiogenesis are poorly defined.

Methods and results

We used an in vitro platform for modeling genotype-correlated drug sensitivity in a panel of 37 GC cell lines in order to test the efficacy of pazopanib, whose clinical activity is not well recognized in GC. 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 µM, while the same treatment of those cell lines without FGFR2 amplification had no growth inhibitory effects. In growth inhibition and colony formation assays using 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) when compared with the NIH-3T3 cells with vectors. Pazopanib also selectively suppressed constitutive FGFR2 signaling and effectively abrogated the baseline phosphorylation of downstream effectors of growth factor receptors such as Erk and Akt in FGFR2-amplified cells. In cell cycle analysis, pazopanib increased a substantial fraction of sub-G1 only in FGFR2-amplified cells. Of the 482 GC specimens from patients, 24 (5%) had an FGFR2 copy number greater than 4.0 copies. However, FGFR2 amplification was not associated with clinicopathological parameters clinical outcomes.

Conclusions

Therefore, these results suggest that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors such as those found in RCC, and should be further explored as a novel therapeutic target in prospective clinical trials.

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