RRC ID 52161
Author Packer LM, Geng X, Bonazzi VF, Ju RJ, Mahon CE, Cummings MC, Stephenson SA, Pollock PM.
Title PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers.
Journal Mol. Cancer Ther.
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 as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1 The 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 FGFR2mutant endometrial 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 FGFR2mutant endometrial 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 regressions in 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 FGFR2mutant endometrial cancer. Mol Cancer Ther; 16(4); 637-48. ©2017 AACR.
Volume 16(4)
Pages 637-648
Published 2017-4
DOI 10.1158/1535-7163.MCT-16-0415
PII 1535-7163.MCT-16-0415
PMID 28119489
MeSH Aminopyridines / administration & dosage* Aminopyridines / pharmacology Animals Antineoplastic Combined Chemotherapy Protocols / administration & dosage* Antineoplastic Combined Chemotherapy Protocols / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Drug Synergism Endometrial Neoplasms / drug therapy* Endometrial Neoplasms / genetics Female Gene Expression Regulation, Neoplastic / drug effects Humans Indazoles / administration & dosage* Indazoles / pharmacology Mice Morpholines / administration & dosage* Morpholines / pharmacology Mutation Phenylurea Compounds / administration & dosage* Phenylurea Compounds / pharmacology Phosphatidylinositol 3-Kinases / antagonists & inhibitors Pyrimidines / administration & dosage* Pyrimidines / pharmacology Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 2 / genetics* Sulfonamides / administration & dosage* Sulfonamides / pharmacology Thiazoles / administration & dosage* Thiazoles / pharmacology Xenograft Model Antitumor Assays
IF 4.856
Resource
Human and Animal Cells JHUEM-2(RCB1551)