title: PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutantEndometrial Cancers.
abstract: Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such asFGFR2, KRAS, PTEN, PIK3CA, andPIK3R1The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2mutantendometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2mutantendometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressionsin vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2mutantendometrial cancer.Mol Cancer Ther; 16(4); 637-48. ©2017 AACR.
authors.affiliation: Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
authors.forename: Leisl M
authors.initials: LM
authors.lastname: Packer
authors.affiliation: Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Geng
authors.affiliation: Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Bonazzi
authors.affiliation: Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ju
authors.affiliation: Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Mahon
authors.affiliation: School of Medicine, University of Queensland Centre for Clinical Research, Queensland, Australia.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Cummings
authors.affiliation: Eph Receptor Biology Group, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Stephenson
authors.affiliation: Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia. pamela.pollock@qut.edu.au.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D009154:Mutation; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000631:Aminopyridines; D007191:Indazoles; D009025:Morpholines; C571178:NVP-BKM120; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013844:Thiazoles; C585539:Alpelisib; C568950:infigratinib; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2