Muvarak Nidal E, Chowdhury Khadiza, Xia Limin, Robert Carine, Choi Eun Yong, Cai Yi, Bellani Marina, Zou Ying, Singh Zeba N, Duong Vu H, Rutherford Tyler, Nagaria Pratik, Bentzen Søren M, Seidman Michael M, Baer Maria R, Lapidus Rena G, Baylin Stephen B, Rassool Feyruz V
Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Cancer Cell. 2016 Oct 10;30(4):637-650. doi: 10.1016/j.ccell.2016.09.002.
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.
聚（ADP - 核糖）聚合酶抑制剂（PARPis）在临床上主要对BRCA突变肿瘤有效。我们基于DNA甲基转移酶（DNMTs）与PARP1之间与DNA损伤相关的结合，引入了一种基于机制的策略来提高PARPi的疗效。在急性髓性白血病（AML）和乳腺癌细胞中，单独使用DNMT抑制剂（DNMTis）可将DNMTs共价结合到DNA中，并增加紧密结合到染色质中的PARP1。与单独使用每种药物相比，低剂量的DNMTis加PARPis可提高PARPi的疗效，增加PARP1在激光诱导的DNA损伤位点的直接积累量和保留时间。这与DNA损伤增加、协同肿瘤细胞毒性、自我更新能力减弱以及在体内对不良AML亚型和BRCA野生型乳腺癌细胞的强烈抗肿瘤反应相关。我们的联合方法引入了一种提高PARPis治疗癌症疗效的策略。
