PT  - JOURNAL ARTICLE
AU  - Gozgit, Joseph M.
AU  - Wong, Matthew J.
AU  - Moran, Lauren
AU  - Wardwell, Scott
AU  - Mohemmad, Qurish K.
AU  - Narasimhan, Narayana I.
AU  - Shakespeare, William C.
AU  - Wang, Frank
AU  - Clackson, Tim
AU  - Rivera, Victor M.
TI  - Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models
AID  - 10.1158/1535-7163.MCT-11-0450
DP  - 2012 Mar 01
TA  - Molecular Cancer Therapeutics
PG  - 690--699
VI  - 11
IP  - 3
4099  - http://mct.aacrjournals.org/content/11/3/690.short
4100  - http://mct.aacrjournals.org/content/11/3/690.full
SO  - Mol Cancer Ther2012 Mar 01; 11
AB  - Members of the fibroblast growth factor receptor family of kinases (FGFR1–4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1–4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC50 values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC50 values <40 nmol/L and inhibited cell growth with GI50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10–30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL–driven models and plasma levels of ponatinib that exceed the IC50 values for FGFR1–4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers. Mol Cancer Ther; 11(3); 690–9. ©2012 AACR.