Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.
Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.
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DOI：
10.1136/gutjnl-2019-319970
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发表时间：
2021-04
期刊：
影响因子：
24.5
通讯作者：
Kleger A
中科院分区：
文献类型：
--
作者：
Gout J;Perkhofer L;Morawe M;Arnold F;Ihle M;Biber S;Lange S;Roger E;Kraus JM;Stifter K;Hahn SA;Zamperone A;Engleitner T;Müller M;Walter K;Rodriguez-Aznar E;Sainz B Jr;Hermann PC;Hessmann E;Müller S;Azoitei N;Lechel A;Liebau S;Wagner M;Simeone DM;Kestler HA;Seufferlein T;Wiesmüller L;Rad R;Frappart PO;Kleger A
ATM丝氨酸/苏氨酸激酶（ATM）是胰腺导管腺癌（PDAC）中最常见的DNA损伤反应基因，参与同源重组（HR）。进行组合协同筛选以努力进行基因型定制的靶向治疗。发现PARP、ATR和DNA-PKcs（PAD）的抑制具有协同作用，导致ATM缺陷型鼠和人PDAC的合成致死率。在机制上，PAD诱导的PARP捕获、复制叉停滞和有丝分裂缺陷导致P53介导的细胞凋亡。最重要的是，ATM的化学抑制使人PDAC细胞对PAD敏感，并在体内长期控制肿瘤。最后，我们通过全外显子组测序预测并阐明了ATM无效背景下的PARP抑制剂耐药性。所产生的细胞是非整倍体的，经历上皮-间充质转化和由于药物转运蛋白上调和DNA修复机制内的旁路而获得的多药耐药（MDR）。这些功能性观察反映在影响5号染色体上包含几个上调的MDR基因的区域的拷贝数变化中。利用这些发现，我们最终提出了替代策略来克服阻力。对PDAC中ATM缺陷引发的分子亲和性的分析允许详细阐述一种有效的突变特异性组合治疗方法，该方法也可以通过ATM抑制以基因型无关的方式实施。
ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC). Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy. Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance. Analysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition.
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影响因子：
13.6
作者：
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DOI：
10.1073/pnas.1605828113
发表时间：
2016-07-26
影响因子：
11.1
作者：
Hamppa, Stephanie;Kiesslinga, Tina;Wiesmueller, Lisa
通讯作者：
Wiesmueller, Lisa