title: Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells.
abstract: OBJECTIVE
  The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. However, certain clinically relevant insights are still lacking. Here we test, while comparing to single agent activity, the olaparib dose and genetic background dependence of olaparib-mediated radiosensitization.
  
  
  METHODS
  Long-term growth inhibition and clonogenic assays were used to assess radiosensitization in BRCA2-deficient and BRCA2-complemented cells and in a panel of human head and neck squamous cell carcinoma cell lines.
  
  
  RESULTS
  The extent of radiosensitization greatly depended on the olaparib dose, the radiation dose and the homologous recombination status of cells. Olaparib concentrations that resulted in radiosensitization prevented PAR induction by irradiation. Seven hours olaparib exposures were sufficient for radiosensitization. Importantly, the radiosensitizing effects can be observed at much lower olaparib doses than the single agent effects.
  
  
  CONCLUSIONS
  Extrapolation of these data to the clinic suggests that low olaparib doses are sufficient to cause radiosensitization, underlining the potential of the treatment. Here we show that drug doses achieving radiosensitization can greatly differ from those achieving single agent activities, an important consideration when developing combined radiotherapy strategies with novel targeted agents.
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Caroline V M
authors.initials: CV
authors.lastname: Verhagen
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: de Haan
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Floor
authors.initials: F
authors.lastname: Hageman
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Tim P D
authors.initials: TP
authors.lastname: Oostendorp
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Annalisa L E
authors.initials: AL
authors.lastname: Carli
authors.affiliation: AstraZeneca, DNA Damage Response Strategic Biology Area, Macclesfield, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Department of Head and Neck Surgery, Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Maxillofacial Surgery, Academic Medical Center, University of Amsterdam, Netherlands.
authors.forename: Michiel W
authors.initials: MW
authors.lastname: van den Brekel
authors.affiliation: Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address: c.vens@nki.nl.
authors.forename: Conchita
authors.initials: C
authors.lastname: Vens
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011829:Radiation Dosage; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C531550:olaparib
keywords: Olaparib (Lynparza™); Optimal biological dose; PARP inhibitor; Radiosensitization; Targeted agent