title: Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models.
abstract: OBJECTIVE
  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.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gozgit
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Squillace
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wongchenko
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.forename: Scott
authors.initials: S
authors.lastname: Wardwell
authors.forename: Qurish
authors.initials: Q
authors.lastname: Mohemmad
authors.forename: Narayana I
authors.initials: NI
authors.lastname: Narasimhan
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000008:administration & dosage; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; C515074:ridaforolimus; C546842:MTOR protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus