Cancer Cell
Volume 30, Issue 4, 10 October 2016, Pages 637-650
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Article
Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer

https://doi.org/10.1016/j.ccell.2016.09.002Get rights and content
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Highlights

  • Low doses of DNMTis in combination with PARPis increase PARP1 binding in chromatin

  • DNMTis and PARPis increase PARP1 and DNMT1 retention at DSBs inducing cytotoxicity

  • The DNMTi-PARPi combination shows strong anti-tumor effects in vivo

  • This paradigm shows PARPis to be a therapeutic option for multiple cancers

Summary

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.

Keywords

AML
breast cancer
PARP
PARP inhibitor
PARP trapping
DNMT1
DNMT inhibitor
DNA double-strand break
DNA damage
DNA repair

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