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Radiosensitization by the PARP inhibitor olaparib in BRCA1-proficient and deficient high-grade serous ovarian carcinomas

  • Yue Bi
    Affiliations
    Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, China

    Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • Ioannis I. Verginadis
    Affiliations
    Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • Souvik Dey
    Affiliations
    Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • Lilie Lin
    Affiliations
    MD Anderson Cancer Center, Division of Radiation Oncology, Houston, TX 77054, USA
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  • Linlang Guo
    Affiliations
    Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, China
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  • Yanfang Zheng
    Correspondence
    Correspondence to: Y. Zheng, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, China.
    Affiliations
    Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, China
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  • Constantinos Koumenis
    Correspondence
    Correspondence to: C. Koumenis, Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Smilow Centre for Translational Research, Room 8-124,3400 Civic Center Blvd., Bldg 421, Philadelphia, PA 19104-5156, USA.
    Affiliations
    Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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      Highlights

      • Olaparib radiosensitizes both BRCA1-deficient and proficient HGSOC.
      • Olaparib-mediated radiosensitization is more in BRCA1-deficient HGSOC than BRCA1-proficient HGSOC.
      • Olaparib inhibits PARP activity, induces more DNA damage and apoptosis when combined with radiotherapy.
      • Olaparib combined with radiotherapy delay tumor growth and prolong survival in HGSOC xenograft mouse model.

      Abstract

      Objective

      Approximately 15–25% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1/2 mutations. Inhibition of Poly (ADP-ribose) polymerase (PARP) is synthetically lethal to cells and tumors with BRCA1/2 mutation. Our goal was to investigate the radiosensitizing effects of PARP inhibitor olaparib in HGSOC with different BRCA1 status.

      Methods

      The radiosensitizing effects of olaparib were tested on BRCA1-proficient and deficient HGSOC by clonogenic survival and tumor growth assays. The effects of olaparib and radiation on DNA damage, PARP activity, and apoptosis were determined.

      Results

      BRCA1-deficient HGSOC cells were more sensitive to RT alone and exhibited significantly higher levels of olaparib-mediated radiosensitization compared to BRCA1-proficient cells. Furthermore, when combined with RT, olaparib inhibited DNA damage repair and PARP1 activity, increased apoptosis, decreased growth of HGSOC xenografts and increased overall host survival. The growth-inhibitory effects of the combined olaparib and RT treatment were more pronounced in mice bearing BRCA1-deficient tumors compared to BRCA1-proficient tumors.

      Conclusions

      These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, particularly in tumors with BRCA1-deficiencies.

      Keywords

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