Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 5, pp 1315–1323 | Cite as

Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models

  • Joseph M. Gozgit
  • Rachel M. Squillace
  • Matthew J. Wongchenko
  • David Miller
  • Scott Wardwell
  • Qurish Mohemmad
  • Narayana I. Narasimhan
  • Frank Wang
  • Tim Clackson
  • Victor M. Rivera
Original Article

Abstract

Purpose

Activating mutations in FGFR2 have been identified as potential therapeutic targets in endometrial cancer, typically occurring alongside genetic alterations that disrupt the mTOR pathway, such as PTEN loss. These observations suggest that the mTOR pathway may act in concert with oncogenic FGFR2 to drive endometrial cancer growth in a subset of patients. The aim of this study was to examine the therapeutic potential of a rational drug combination based on the simultaneous targeting of mutant-FGFR2 and mTOR-driven signaling pathways in endometrial cancer cells.

Methods

Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. Ridaforolimus is a selective inhibitor of mTOR that has demonstrated positive clinical activity in endometrial cancer. The combinatorial effects of ponatinib and ridaforolimus on growth of endometrial cancer models, and their modes of action, were evaluated in vitro and in vivo.

Results

The combination of ponatinib and ridaforolimus had a synergistic effect on the in vitro growth of endometrial lines bearing an activating FGFR2 mutation, irrespective of PTEN status. Concomitant inhibition of both FGFR2 and mTOR signaling pathways was observed, with simultaneous blockade resulting in enhanced cell cycle arrest. Ponatinib and ridaforolimus each demonstrated inhibition of tumor growth in vivo, but dual inhibition by the combination of agents resulted in superior efficacy and induced tumor regression in an endometrial xenograft.

Conclusions

These encouraging preclinical findings suggest the inhibition of both FGFR2 and mTOR by the ponatinib–ridaforolimus combination may provide a new therapeutic strategy to treat advanced endometrial cancers with dual pathway dysregulation.

Keywords

FGFR2 mTOR Endometrial cancer Ponatinib Ridaforolimus 

Notes

Conflict of interest

All authors except Matthew Wong are current employees of ARIAD Pharmaceuticals, Inc. All authors have stock ownership.

Supplementary material

280_2013_2131_MOESM1_ESM.pptx (75 kb)
Figure 1. Body weight measurement of mice dosed with ponatinib and ridaforolimus combination in vivo. Mice bearing AN3CA endometrial xenografts (200 mm3) were randomized into treatment groups (n = 10 mice/group). Mice were administered vehicle, ponatinib at 10 mg/kg or 30 mg/kg, ridaforolimus at 0.3 mg/kg or 1 mg/kg, or a combination of ponatinib and ridaforolimus. A) Low dose ponatinib (10 mg/kg), administered alone or in combination with ridaforolimus. B) High dose ponatinib (30 mg/kg), administered alone or in combination with ridaforolimus. Vehicle and ridaforolimus administered alone, at 0.3 or 1 mg/kg, are shown in both panels (A + B). Ridaforolimus was administered for 5 days followed by a two day break (QDX5) (gray line), and ponatinib was administered daily (black line). Three cycles of dosing were completed. (PPTX 75 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Joseph M. Gozgit
    • 1
  • Rachel M. Squillace
    • 1
  • Matthew J. Wongchenko
    • 1
  • David Miller
    • 1
  • Scott Wardwell
    • 1
  • Qurish Mohemmad
    • 1
  • Narayana I. Narasimhan
    • 1
  • Frank Wang
    • 1
  • Tim Clackson
    • 1
  • Victor M. Rivera
    • 1
  1. 1.ARIAD Pharmaceuticals, Inc.CambridgeUSA

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