title: The allosteric AKT inhibitor, MK2206, decreases tumor growth and invasion in patient derived xenografts of endometrial cancer.
abstract: The purpose of this study was to test the effect of MK2206, an allosteric inhibitor of AKT, on the growth and invasion of patient-derived xenografts (PDX) of endometrial cancer. Three PDX lines, USC1 (uterine serous), EEC2 (endometrioid grade 2) and EEC4 (endometrioid grade 3) of endometrial cancer were grafted under the renal capsule of NSG mice. After 2 weeks of tumor growth the mice were treated with vehicle or 120mg/kg MK2206 twice a week for 3 weeks. Growth of all 3 PDX lines of different type and grade was significantly inhibited in response to MK2206 compared with vehicle control. Histological analysis revealed invasion and spread of EEC2 and EEC4 tumors were significantly decreased with MK2206 treatment. Immunohistochemical analysis showed a decrease in Ki67 in EEC2 upon MK2206 treatment, while USC1 and EEC4 tumors did not show differences in Ki67 levels. PR levels were evident in EEC2 which dramatically increased upon MK2206 treatment. In vitro analysis of EEC4 and AN3CA cells showed a dose-dependent decrease in p(Ser473)-AKT and p(Thr308)-AKT with MK2206. Invasion of EEC4 and AN3CA cells also significantly decreased after 36h and 72h of MK2206 treatment. PDX tumors provide an appropriate model for the testing of compounds that incorporates the heterogeneous nature of endometrial cancer. Further studies to determine efficacy of MK2206 alone or in combination with other compounds can also identify predictors of response to these pathway inhibitors.
authors.affiliation: a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology , Northwestern University , Chicago , IL , USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Winder
authors.affiliation: b Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology , Northwestern University , Chicago , IL , USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Unno
authors.affiliation: b Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology , Northwestern University , Chicago , IL , USA.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Yu
authors.affiliation: a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology , Northwestern University , Chicago , IL , USA.
authors.forename: John
authors.initials: J
authors.lastname: Lurain
authors.affiliation: b Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology , Northwestern University , Chicago , IL , USA.
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; endometrial cancer; patient derived xenografts