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

Gynecologic Oncology
Yue BiConstantinos Koumenis

Abstract

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. 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. 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. These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, p...Continue Reading

Citations

May 11, 2019·Future Oncology·Eleonora GhisoniGiorgio Valabrega
Jul 8, 2020·Cancers·Ana Beatriz VarandaRita Fior
Apr 12, 2020·Cancers·Elena VagiaMassimo Cristofanilli
Mar 21, 2020·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Lilie L LinAnuja Jhingran
Aug 16, 2019·Molecular Cancer Therapeutics·Anna R MichmerhuizenCorey Speers
Nov 2, 2019·Hematology/oncology Clinics of North America·Deborah E Citrin
Jan 30, 2020·Clinical and Translational Radiation Oncology·David S LakomyLilie L Lin
Jul 1, 2020·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Moataz RedaWassana Yantasee

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