Abstract
DS-7423, a novel, small-molecule dual inhibitor of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR), is currently in phase I clinical trials for solid tumors. Although DS-7423 potently inhibits PI3Kα (IC50 = 15.6 nM) and mTOR (IC50 = 34.9 nM), it also inhibits other isoforms of class I PI3K (IC50 values: PI3Kβ = 1,143 nM; PI3Kγ = 249 nM; PI3Kδ = 262 nM). The PI3K/mTOR pathway is frequently activated in ovarian clear cell adenocarcinomas (OCCA) through various mutations that activate PI3K-AKT signaling. Here, we describe the anti-tumor effect of DS-7423 on a panel of nine OCCA cell lines. IC50 values for DS-7423 were <75 nM in all the lines, regardless of the mutational status of PIK3CA. In mouse xenograft models, DS-7423 suppressed the tumor growth of OCCA in a dose-dependent manner. Flow cytometry analysis revealed a decrease in S-phase cell populations in all the cell lines and an increase in sub-G1 cell populations following treatment with DS-7423 in six of the nine OCCA cell lines tested. DS-7423-mediated apoptosis was induced more effectively in the six cell lines without TP53 mutations than in the three cell lines with TP53 mutations. Concomitantly with the decreased phosphorylation level of MDM2 (mouse double minute 2 homolog), the level of phosphorylation of TP53 at Ser46 was increased by DS-7423 in the six cell lines with wild-type TP53, with induction of genes that mediate TP53-dependent apoptosis, including p53AIP1 and PUMA at 39 nM or higher doses. Our data suggest that the dual PI3K/mTOR inhibitor DS-7423 may constitute a promising molecular targeted therapy for OCCA, and that its antitumor effect might be partly obtained by induction of TP53-dependent apoptosis in TP53 wild-type OCCAs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma, Clear Cell / drug therapy
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Adenocarcinoma, Clear Cell / enzymology
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Adenocarcinoma, Clear Cell / genetics
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Adenocarcinoma, Clear Cell / pathology*
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Class I Phosphatidylinositol 3-Kinases
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DNA Mutational Analysis
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Female
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Flow Cytometry
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mice, Nude
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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P53AIP1 protein, human
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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RNA, Messenger
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Tumor Suppressor Protein p53
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Phosphoserine
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MTOR protein, human
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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TOR Serine-Threonine Kinases
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Sirolimus
Grants and funding
This work was supported by Daiichi Sankyo Co. Ltd., The Grant-in-Aid for Scientific Research (C), Grant Number 19599005 and 23592437 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to K Oda). This study was also performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan (to T Yano). Yoshinobu Shiose and Yasuhide Hirota, employees of Daiichi Sankyo Co. Ltd, contributed to the experiments (in vivo experiments) as listed in the “contributions” of each author. The funders themselves had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.