Abstract
Abstract Introduction: Members of the fibroblast growth factor receptor family (FGFR1-4) are mutationally-activated in a number of tumor types. A broad array of mutations have been observed that likely activate through different mechanisms, given the disparate functions of the domains they are found in: the ligand binding (LB) domain, the extracellular (EC) domain that effects receptor dimerization, the transmembrane (TM) domain, and the kinase domain (KD). FGFR2 is mutated in 10% of endometrial cancers, with 90% of all mutations found at six specific codons. In addition, mutations have been found in 12% of lung squamous cell carcinomas (SCCs; FGFR1-4), 50% of bladder cancers (FGFR3), and in glioblastoma multiforme (GBM; FGFR1). Ponatinib (AP24534) is an oral multi-targeted kinase inhibitor being developed for the treatment of CML or Ph+ ALL. Previously, ponatinib was shown to also be a potent inhibitor of all 4 FGFRs, inhibiting viability of Ba/F3 cells dependent on activated variants of native FGFR1-4 (via fusion to a TEL dimerization domain) with IC50s of 14-47 nM. Similar potency was observed in HEK cells transiently transfected to overexpress full-length FGFR1-3, as measured by inhibition of FGFR phosphorylation (IC50s 15-35 nM). Here, the HEK cell system was used to test the ability of ponatinib to inhibit a broad panel of naturally-occurring mutant variants of FGFR1-3, with a primary focus on mutant variants of FGFR2 that have been observed in endometrial and/or SCCs. Results: Of 12 FGFR2 mutants tested, ponatinib inhibited the activity of 10 with high potency and 2 with moderate potency. The 10 mutants inhibited most potently (IC50s < 45 nM) included the 2 mutants that together account for over half of those observed in endometrial cancer (S252W and N550K) and included mutants located in all 4 functional domains: the LB domain (S252W and P253R), the EC domain (Y376C and W290C), the TM domain (C383R), and the KD (I548V, N550K, G584W, K660N and R738K). The 2 FGFR2 mutants inhibited with moderate potency (IC50: 113-152 nM) were N550H and K660E. Select mutant versions of FGFR1 and 3 were also examined. Ponatinib had moderate potency against the FGFR3-S249C EC domain mutant (IC50 128 nM) commonly found in bladder cancer, and did not inhibit the less common K652E KD mutant. Ponatinib potently inhibited the FGFR1-N546K KD mutant found in GBM (IC50 18 nM). Importantly, in patients dosed once daily at 45 mg with ponatinib, peak and trough concentrations are 145 nM and 64 nM, respectively. These exposure levels exceed the IC50s for most mutants tested here. Conclusion: Ponatinib potently inhibited the activity of a broad spectrum of FGFR mutant variants, including FGFR2 mutants observed in endometrial and SCCs. Most of the mutant variants were inhibited at concentrations shown to be achievable in the clinic. These results provide strong support for clinical evaluation of ponatinib in FGFR-driven cancers. Citation Format: Alexa B. Schrock, Joseph M. Gozgit, Tim Clackson, Victor M. Rivera. Ponatinib potently inhibits the activity of mutant variants of FGFR commonly found in endometrial, lung and other cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2083. doi:10.1158/1538-7445.AM2013-2083
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