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The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis

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Abstract

Purpose

The PI3K/AKT/mTOR pathway is one of the most highly activated cellular signaling pathways in advanced ovarian cancer. Although several PI3K/AKT/mTOR inhibitors have been developed to treat various types of cancer, the antitumor efficacy of many of these compounds against ovarian cancer has remained unclear.

Methods

Here, we tested and compared a panel of 16 PI3K/AKT/mTOR inhibitors (XL765, Miltefosine, Rapamycin, CCI-779, RAD001, FK506, XL147, GSK2110183, IPI-145, GSK2141795, BYL719, GSK458, CAL-101, XL765 analogue SAR245409, Triciribine, and GDC0941) that have entered clinical trials for antitumor activity against ovarian cancer, as well as the front line drug, paclitaxel. Antitumor efficacy was measured in both ovarian cancer cell lines and patient-derived ovarian primary tumor cell lines in vitro and in vivo.

Results

We identified the PI3K/mTOR dual inhibitor GSK458 as a potent inhibitor of proliferation in all cell lines tested at half maximal inhibitory concentrations (IC50) of approximately 0.01-1 µM, a range tens to hundreds fold lower than that of the other PI3K/AKT/mTOR inhibitors tested. Additionally, GSK458 showed the highest inhibitory efficacy against ovarian cancer cell migration. GSK458 also inhibited tumor growth and metastasis in nude mice intraperitoneally engrafted with SKOV3 cells or a patient-derived tumor cell xenograft (PDCX). Importantly, the inhibitory efficiency of GSK458 on cell proliferation and migration both in vitro and in vivo was comparable to that of paclitaxel. Mechanistically, the anti-tumor activity of GSK458 was found to be associated with inactivation of AKT and mTOR, and induction of cell cycle arrest at the G0/G1 phase.

Conclusions

Based on our results, we conclude that GSK458 may serve as an attractive candidate to treat ovarian cancer.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81702563 to Y.J.X., and 81472445 and 81672587 to R.Z.), the Postdoctoral Science Foundation of China (Grant No. 2019M652850 to Y.J.X.) and the Scientific and Technological Innovation Act Program of the Shanghai Science and Technology Commission (Grant No. 4411973100 to R.Z.).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Southern Medical University, 201499, Shanghai, China

    Yangjiong Xiao & Rong Zhang

  2. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 510182, Guangzhou, China

    Yangjiong Xiao

  3. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Yangjiong Xiao

  4. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China

    Yangjiong Xiao & Yang Yu

  5. Department of Gynecology, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, 213004, China

    Pengcheng Jiang

  6. Department of Gynecology, The International Peace Maternity & Child Health Hospital, The China Welfare Institute, Shanghai Jiaotong University, Shanghai, 200030, China

    Yuhong Li & Chao Wang

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Correspondence to Yangjiong Xiao or Rong Zhang.

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Written informed consent was obtained from all individual participants according to the Declaration of Helsinki. This study was carried out in accordance with the recommendations of, and approval by the Ethical Committee of Fengxian District Central Hospital. All animal experimental procedures described in this study were performed according to the Guidelines for the care and use of animals established by the Laboratory Animal Ethical Board and approved by the Animal Care and Use committee of the East China Normal University School of Life Sciences.

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Xiao, Y., Yu, Y., Jiang, P. et al. The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis. Cell Oncol. 43, 669–680 (2020). https://doi.org/10.1007/s13402-020-00514-8

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