Abstract B236: Pazopanib, a novel multitargeted kinase inhibitor, shows potent in vitro antitumor activity in gastric cancer cell lines harboring FGFR2 amplification, which is a potential therapeutic target in gastric cancer.

Abstract

Abstract Background: Identification of critical genes which play pivotal role in controlling tumor growth and survival will establish the basis for developing therapeutic targets. However, these approaches have not been extensively studied in gastric cancer (GC). The fibroblast growth factor receptor (FGFR) tyrosine kinase family has long been implicated in cancer. Among them, recent studies have shown that activating somatic mutations in FGFR2 are correlated with sensitivity to FGFR2 kinase inhibition in the cell lines bearing such FGFR2 mutations, implicating FGFR2 as a novel therapeutic target. Pazopanib is an orally bioavailable, ATP competitive, multi-targeted kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, which results in selectively inhibiting VEGF-induced angiogenesis. However, the biologic sequences of pazopanib activities beyond anti-angiogenesis are poorly defined. Method and Results: Using our in vitro platform for modeling the genotype-correlated drug sensitivity in a panel of 37 GC cell lines, we performed this preclinical study to test the efficacy of pazopanib, whose clinical activity is not well recognized in gastric cancer. In growth inhibition assay, pazopanib showed differential effect on cell growth according to the genomic changes. Treatment of the KATO-III, OCUM-2M, SNU-16 and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in a marked decrease in cell survival with IC50 in ranges of 0.1 ∼ 2.0 μM, respectively, while same treatment of the cell lines without FGFR2 amplification had no growth inhibitory effect. In growth inhibition and colony formation assay using ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by the FGFR2-expressing NIH 3T3 cells with WT FGFR2 and mutant FGFR2 (S252W), as compared with the NIH-3T3 cell with vector. Pazopanib also selectively suppressed the constitutive FGFR2 signaling 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, the FGFR2-amplified cells underwent cell cycle arrest at the G1-S phase after pazopanib treatment, whereas no significant effect on cell cycle progression in cells without FGFR2 amplification treated with pazopanib. Also, only in the FGFR2-amplified cells did pazopanib increase a substantial fraction of sub-G1. Conclusion: Taken together, our findings show activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in the small subset of GC patients and may sensitize these cancer cells to pazopanib. Therefore these results suggest that pazopanib may provide genotype-correlated clinical benefit beyond the setting of highly vascular tumor like RCC, which should be further explored as a novel therapeutic target in prospective clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B236.