Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer |
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Institution: | 1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, United States of America;2. Department of Pathology, University of Washington, Seattle, WA 98195, United States of America;1. Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway;2. Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway;3. University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316 Oslo, Norway;1. University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA;2. Memorial Sloan Kettering Cancer Center, New York, NY, USA;3. The University of Chicago Medicine, Chicago, IL, USA;4. City of Hope National Medical Center, Duarte, CA, USA;5. AbbVie Inc., North Chicago, IL, USA;6. Fox Chase Cancer Center, Philadelphia, PA, USA |
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Abstract: | Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer. |
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Keywords: | PI3K/AKT/mTOR pathway DNA damage response Cell cycle checkpoint DNA repair Ovarian cancer |
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