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

Yue Bi1, Ioannis I Verginadis2, Souvik Dey2

  • 1Oncology 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.

Gynecologic Oncology
|July 21, 2018
PubMed
Abstract

Insights

Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib enhances radiation therapy (RT) in high-grade serous ovarian carcinomas (HGSOC). BRCA1-deficient tumors showed greater sensitivity to olaparib and RT, indicating improved treatment potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • High-grade serous ovarian carcinomas (HGSOC) often harbor BRCA1/2 mutations.
  • Poly (ADP-ribose) polymerase (PARP) inhibition is synthetically lethal in BRCA1/2-mutated cancers.
  • Olaparib is a PARP inhibitor with potential therapeutic applications.

Purpose of the Study:

  • To investigate the radiosensitizing effects of olaparib in HGSOC.
  • To compare the efficacy of olaparib and radiation in BRCA1-proficient versus BRCA1-deficient HGSOC.
  • To evaluate the impact of olaparib on DNA damage repair and apoptosis in HGSOC.

Main Methods:

  • Clonogenic survival and tumor growth assays were used to assess radiosensitization.
  • BRCA1-proficient and BRCA1-deficient HGSOC cell lines and xenografts were utilized.
  • Effects on DNA damage, PARP activity, and apoptosis were quantified.

Main Results:

  • BRCA1-deficient HGSOC exhibited increased sensitivity to radiation alone and greater radiosensitization with olaparib.
  • Combined olaparib and radiation therapy inhibited DNA repair and PARP1 activity.
  • Olaparib plus radiation increased apoptosis, reduced tumor growth, and improved survival in preclinical models, especially in BRCA1-deficient tumors.

Conclusions:

  • Olaparib demonstrates significant radiosensitizing effects in HGSOC.
  • The combination of olaparib and radiation therapy shows promise for treating HGSOC, particularly those with BRCA1 deficiencies.
  • These findings support olaparib as a radiosensitizer for improved HGSOC treatment strategies.
Keywords:
BRCA1HGSOCPARP inhibitorRadiosensitizationRadiotherapy

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