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
Publish Date: 2013/03/07
Volume: 71, Issue: 5, Pages: 1315-1323
Abstract
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 mutantFGFR2 and mTORdriven signaling pathways in endometrial cancer cellsPonatinib 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 vivoThe 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
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