| Literature DB >> 27728808 |
Nidal E Muvarak1, Khadiza Chowdhury1, Limin Xia2, Carine Robert1, Eun Yong Choi3, Yi Cai2, Marina Bellani4, Ying Zou5, Zeba N Singh5, Vu H Duong3, Tyler Rutherford6, Pratik Nagaria1, Søren M Bentzen7, Michael M Seidman4, Maria R Baer8, Rena G Lapidus3, Stephen B Baylin9, Feyruz V Rassool10.
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.Entities:
Keywords: AML; DNA damage; DNA double-strand break; DNA repair; DNMT inhibitor; DNMT1; PARP; PARP inhibitor; PARP trapping; breast cancer
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Year: 2016 PMID： 27728808 PMCID： PMC5201166 DOI： 10.1016/j.ccell.2016.09.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743