Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma

• Published in: Gynecologic oncology 2019-11, Vol.155 (2), p.331-339
• Main Authors: Makii, Chinami, Ikeda, Yuji, Oda, Katsutoshi, Uehara, Yuriko, Nishijima, Akira, Koso, Takahiro, Kawata, Yoshiko, Kashiyama, Tomoko, Miyasaka, Aki, Sone, Kenbun, Tanikawa, Michihiro, Tsuruga, Tetsushi, Mori-Uchino, Mayuyo, Nagasaka, Kazunori, Matsumoto, Yoko, Wada-Hiraike, Osamu, Kawana, Kei, Hasegawa, Kosei, Fujiwara, Keiichi, Aburatani, Hiroyuki, Osuga, Yutaka, Fujii, Tomoyuki
• Format: Article
• Language: English
• Subjects: Clear cell ovarian carcinoma; Hematology, Oncology, and Palliative Medicine; MDM2; Molecular targeted therapy; Obstetrics and Gynecology; Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway; Prognosis
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2019.08.028

AbstractIntroductionPI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2. Materials and methodscDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry. ResultsTumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs ( P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice ( P