Ponatinib (AP24534), a multi-targeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models
Menée sur 14 lignées cellulaires représentant divers types de cancer et à l'aide de modèles murins, cette étude évalue l'activité du ponatinib, un inhibiteur de l'activité tyrosine kinase des récepteurs de la famille FGFR
Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multi-targeted tyrosine kinase inhibitor (TKI) being explored in a pivotal phase 2 trial in patients with chronic mylogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all 4 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 IC50s <40 nM, 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 IC50s <40 nM and inhibited cell growth with GI50s of 7-181 nM. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all 3 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 IC50s for FGFR1-4 inhibition can be sustained in patients. These results demonstrate that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.
http://mct.aacrjournals.org/content/early/2012/01/10/1535-7163.MCT-11-0450.abstract