Hypoxia potentiates the radiosensitizing effect of olaparib in human non-small cell lung cancer xenografts by contextual synthetic lethality

Publication date: Available online 23 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Yanyan Jiang, Tom Verbiest, Aoife M. Devery, Sivan M. Bokobza, Anika M. Weber, Katarzyna B. Leszczynska, Ester M. Hammond, Anderson J. Ryan
PurposePoly(ADP-ribose) polymerase (PARP) inhibitors potentiate radiotherapy in preclinical models of human non-small-cell lung cancer (NSCLC) and other types of cancer. However, the mechanisms underlying radiosensitization in vivo are incompletely understood. Herein, we investigated the impact of hypoxia on radiosensitization by the PARP inhibitor olaparib in human NSCLC xenograft models.Methods and MaterialsNSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O2) or hypoxic (1% O2) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 h or 72 h after the first treatment. Immunohistochemistry was performed to assess hypoxia (carbonic anhydrase IX (CA9)), vessels (CD31), DNA double strand breaks (DSB) (γH2AX), and apoptosis (cleaved caspase 3 (CC3)). The remaining xenografts (n=6/group) were monitored for tumor growth.ResultsIn vitro, olaparib showed a greater radiosensitizing effect on Calu-3 and Calu-6 cells in hypoxic conditions (1% O2). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<0.001) and apoptosis (P<0.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in non-hypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<0.001) but not in Calu-3 tumors.ConclusionsOur data suggest that hypoxia potentiates the radiosensitizing effects of olaparib by contextual synthetic killing, and that tumor hypoxia may be a potential biomarker for selecting patients who may get the greatest benefit from the addition of olaparib to radiotherapy.

Teaser

We show that the PARP inhibitor olaparib enhances radiation-induced DNA damage response in the hypoxic tumor cells of Calu-6 xenografts, but not in the non-hypoxic tumor cells of Calu-6 xenografts or in the tumor cells of well-oxygenated Calu-3 xenografts. Consequently, olaparib potentiates the anti-tumor effect of radiation in hypoxic tumors, but not in well-oxygenated tumors. This suggests that hypoxia enhances the radiosensitizing effects of olaparib in human non-small-cell lung cancer (NSCLC) xenografts by contextual synthetic lethality.


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