Background: Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) with potent activity against BCR-ABL being investigated in a pivotal phase 2 trial in patients with chronic myeloid leukemia (CML). Previously, ponatinib has been shown to potently inhibit FGFR1-4 kinase activity. Here the activity of ponatinib is explored against FGFR1-4 activated via multiple discrete mechanisms in a variety of cancer types in vitro and in vivo.

Results: The cellular activity of ponatinib was first examined in Ba/F3 cells engineered to express activated FGFRs. Ponatinib selectively inhibited viability of cells expressing FGFR1-4, with IC50s of 8 to 34 nM, while having no effect on viability of parental Ba/F3 cells (IC50 >1000 nM). Likewise, ponatinib inhibited phosphorylation of FGFR1-4 with IC50s of 29 to 39 nM. Four other TKIs in clinical development that have been reported to have anti-FGFR activity were substantially less potent: dovitinib (IC50: 34 to 235 nM), cediranib (54 to >1000 nM), BIBF 1120 (214 to >1000 nM) and brivanib (503 to >1000 nM). Next the activity of ponatinib was examined in a panel of cell lines representing multiple tumor types and containing FGFRs dysregulated by a variety of mechanisms. Ponatinib potently inhibited growth of breast cancer cells containing amplified FGFR1 or FGFR2 (GI50: 14-69 nM) and of gastric cancer cells with amplified FGFR2 (GI50: 10-25 nM). In endometrial cancer cells with an activating mutation in the kinase domain of FGFR2 (N549K), or a mutation that increases ligand binding (S252W), ponatinib inhibited growth with GI50s of 14-61 nM. In bladder cancer cells with a mutation in FGFR3 that causes constitutive dimerization (S249C), ponatinib inhibited growth with GI50s of 103-181 nM. In all cell lines, the effects on cell growth were accompanied by inhibition of FGFR or FRS2α phosphorylation. In comparison, ponatinib was less potent in a panel of cell lines lacking expression of activated FGFRs (GI50: 372 nM to >1 uM). The 4 other TKIs examined were less active compared to ponatinib in all FGFR mutant cell lines examined. Daily oral dosing of ponatinib (30 mg/kg) to mice reduced growth of FGFR2N549K endometrial and FGFR3S249C bladder tumor xenografts by approximately 80% and induced regression of gastric tumors expressing amplified FGFR2 by 50%. In all 3 models, dose-dependent inhibition of FGFR phosphorylation in the tumor was demonstrated.

Conclusion: Ponatinib exhibits potent, pan-FGFR inhibitory activity that compares favorably to dovitinib, cediranib, BIBF 1120 and brivanib. These results provide a strong rationale for clinical evaluation of ponatinib in FGFR-driven cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3560. doi:10.1158/1538-7445.AM2011-3560