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01-05-2013 | Original Article

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

Authors: 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

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2013

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.

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Title: Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models
Authors: 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
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2131-z

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