Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Abstract

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 IC 50 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 IC 50 values <40 nmol/L and inhibited cell growth with GI 50 (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 IC 50 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.

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…Furthermore, it has been shown to be a potent pan-FGFR inhibitor in preclinical assays. Remarkably, it was able to inhibit in vitro cell proliferation and signaling in various cell lines characterized either by FGFR amplifi cations or activating mutations ( 81 ). These recent data highlight the rationale to investigate ponatinib as a potential treatment for FGFR-driven solid tumors as well.…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…Moreover, an in vitro study has been analyzing the possibility of using Ponatinib in cancer cell lines of endometrial, bladder, gastric, breast, lung and colon cancer harboring FGFR1-4 alterations. The results are very promising since Ponatinib shows specific activity against the four receptors and it seems to work like a FGFR-pan-inhibitor (Gozgit et al, 2012). Currently, they are trying to discover novel Ponatinb anologues to reduce kinase insert domain receptor (KDR) activities (Yang et al, 2017) (I would delete this sentence).…”

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Among them, regorafenib is a novel orally active multitarget compound that inhibits a number of pro-angiogenic TK receptors, including FGFR1, VEGFR2, TIE2, and PDGFR [143]; nintedanib (BIBF1120) interferes with VEGFR, PDGFR and FGFR pathways [144]; ponatinib (AP24534), mainly active on BCR-ABL, has been described to exert an anti-FGFR activity in vitro [145]. Several other small molecules, including axitinib, brivanib, cabozantinib, dovotinib, oratinib, pazopamib, sorafenib, sunitinib and vandetanib are endowed with this non-selective TKI profile (see Refs.…”