RT Journal Article
SR Electronic
T1 Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 690
OP 699
DO 10.1158/1535-7163.MCT-11-0450
VO 11
IS 3
A1 Gozgit, Joseph M.
A1 Wong, Matthew J.
A1 Moran, Lauren
A1 Wardwell, Scott
A1 Mohemmad, Qurish K.
A1 Narasimhan, Narayana I.
A1 Shakespeare, William C.
A1 Wang, Frank
A1 Clackson, Tim
A1 Rivera, Victor M.
YR 2012
UL http://mct.aacrjournals.org/content/11/3/690.abstract
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.