Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer

• Published in: Gynecologic oncology Vol. 133; no. 2; pp. 346 - 352
• Main Authors: Bradford, Leslie S, Rauh-Hain, Alejandro, Clark, Rachel M, Groeneweg, Jolijn W, Zhang, Ling, Borger, Darrell, Zukerberg, Lawrence R, Growdon, Whitfield B, Foster, Rosemary, Rueda, Bo R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2014
• Subjects: Aminopyridines - administration & dosage; Aminopyridines - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Carboplatin - administration & dosage; Carcinoma, Endometrioid - genetics; Carcinoma, Endometrioid - metabolism; Carcinosarcoma - genetics; Carcinosarcoma - metabolism; Class I Phosphatidylinositol 3-Kinases; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Female; Hematology, Oncology and Palliative Medicine; Humans; Mice; Mice, SCID; Morpholines - administration & dosage; Morpholines - pharmacology; Mutation; Obstetrics and Gynecology; Paclitaxel - administration & dosage; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - metabolism; Phosphatidylinositol 3-Kinases - genetics; PI3K inhibitor; PI3K/AKT/mTOR pathway; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - drug effects; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays; Endometrial cancer; PI3K/AKT/mTOR pathway; PI3K inhibitor
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2014.02.022

Abstract Objective Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C + BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Results In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5–10 compared to the linear growth observed in vehicle treated tumors (p < 0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p < 0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p < 0.05). Synergistic tumor growth suppression (p < 0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. Conclusion Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.