Research ArticleCancer

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

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Science Translational Medicine  15 May 2019:
Vol. 11, Issue 492, eaav4508
DOI: 10.1126/scitranslmed.aav4508

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The secret life of cediranib

Anti-angiogenic agents are used to inhibit the formation of new blood vessels that supply nutrition and oxygen to tumors, but recent findings suggest that they can have additional anticancer effects. In particular, a clinical study unexpectedly found that the anti-angiogenic drug cediranib can sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibitors, which normally target tumors with defective DNA repair. Kaplan et al. determined that cediranib not only damages tumors by interrupting their blood supply and thereby inducing hypoxia but also directly affects pathways involved in DNA repair, sensitizing cancer cells to PARP inhibitors and suggesting a strategy for targeted treatment.

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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