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Sci Transl Med. 2019 May 15;11(492). pii: eaav4508. doi: 10.1126/scitranslmed.aav4508.

Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51.

Author information

1
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA.
2
Department of Pathology, Yale University School of Medicine, New Haven, CT 06511, USA.
3
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA. peter.glazer@yale.edu.
4
Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, USA.

Abstract

Combining the anti-angiogenic agent cediranib with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib improves progression-free survival compared to olaparib alone in ovarian cancer patients through an unknown mechanism. PARP inhibitors are used primarily in the treatment of patients with DNA repair-associated (BRCA1/2) mutated cancers because these mutations cause a deficit in homology-directed DNA repair (HDR) that confers sensitivity to these agents. However, the combination of cediranib and olaparib was effective in patients without BRCA1/2 mutations. We report here that cediranib confers sensitivity to olaparib by down-regulating HDR in tumor cells. This occurs partially as a result of cediranib inducing hypoxia, which suppresses expression of the HDR factors BRCA1/2 and RAD51 recombinase (RAD51). However, we also observed that cediranib has a direct effect on HDR independent of its ability to induce tumor hypoxia. This direct effect occurs through platelet-derived growth factor receptor (PDGFR) inhibition, activation of protein phosphatase 2A (PP2A), and E2F transcription factor 4 (E2F4)/RB transcriptional corepressor like 2 (RB2/p130)-mediated repression of BRCA1/2 and RAD51 gene expression. This down-regulation was seen in mouse tumor xenografts but not in mouse bone marrow, providing a therapeutic window for combining cediranib and olaparib in cancer therapy. Our work reveals a treatment strategy by which DNA repair can be manipulated in human tumors to induce synthetic lethality, broadening the potential therapeutic scope of cediranib based on its activity as a DNA repair inhibitor.

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