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

Authors: Kaplan, Alanna R; Gueble, Susan E; Liu, Yanfeng; Oeck, Sebastian; Kim, Hoon; Yun, Zhong; Glazer, Peter M

Published In Sci Transl Med, (2019 05 15)

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.

PubMed ID: 31092693

MeSH Terms: Animals; BRCA1 Protein/metabolism*; BRCA2 Protein/metabolism*; Cell Line, Tumor; DNA Repair/drug effects*; Down-Regulation/drug effects*; E2F4 Transcription Factor/metabolism; Female; Gene Expression Regulation, Neoplastic/drug effects; Humans; Mice, Nude; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology; Quinazolines/pharmacology*; Rad51 Recombinase/metabolism*; Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor/metabolism; Tumor Hypoxia/drug effects; Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2/metabolism; Xenograft Model Antitumor Assays