Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment.
Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment.
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DOI：
10.18632/oncotarget.3307
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发表时间：
2015-04-30
期刊：
影响因子：
--
通讯作者：
Gewinner CA
中科院分区：
文献类型：
--
作者：
Ip LR;Poulogiannis G;Viciano FC;Sasaki J;Kofuji S;Spanswick VJ;Hochhauser D;Hartley JA;Sasaki T;Gewinner CA
卵巢癌患者的治疗选择仍然有限，尽管最近临床取得了进展，但总存活率不到50%。脂肪磷酸酶多聚磷酸肌醇4-磷酸酶(INPP4B)被认为是PI3K/Akt途径中的一种肿瘤抑制因子，在乳腺癌、卵巢癌和黑色素瘤中表达缺失最为明显。利用基因芯片技术，我们在INPP4B缺陷细胞中发现了一种DNA修复缺陷，并通过彗星实验和γH_2AX、RAD51和53BP1焦点的形成进行了进一步的表征。在二维和三维体外模型以及体内异种移植模型中，INPP4B缺失导致对PARP抑制的敏感性显著增加，与BRCA1缺失相当。在GST下拉和293T过表达实验中，我们发现INPP4B与DNA修复的关键分子ATR和BRCA1形成蛋白质复合体，INPP4B缺失影响BRCA1、ATM和ATR蛋白的稳定性，导致观察到的DNA修复缺陷。鉴于在40%的卵巢癌患者中发现了INPP4B缺失，这项研究为将INPP4B作为PARP抑制反应的生物标志物提供了理论基础，并因此为相当一部分患者提供了新的治疗选择。肿瘤抑制因子肌醇多聚磷酸酶II(INPP4B)的缺失会导致BRCA1、ATR和ATM的缺失，从而导致DNA修复缺陷，并可作为PARP抑制剂的治疗靶点。
Treatment options for ovarian cancer patients remain limited and overall survival is less than 50% despite recent clinical advances. The lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) has been described as a tumor suppressor in the PI3K/Akt pathway with loss of expression found most pronounced in breast, ovarian cancer and melanoma. Using microarray technology we identified a DNA repair defect in INPP4B-deficient cells, which we further characterized by comet assays and quantification of γH2AX, RAD51 and 53BP1 foci formation. INPP4B loss resulted in significantly increased sensitivity towards PARP inhibition, comparable to loss of BRCA1 in two- and three-dimensional in vitro models, as well as in in vivo xenograft models. Mechanistically, we discovered that INPP4B forms a protein complex with the key players of DNA repair, ATR and BRCA1, in GST pulldown and 293T overexpression assays, and INPP4B loss affects BRCA1, ATM and ATR protein stability resulting in the observed DNA repair defect. Given that INPP4B loss has been found in 40% of ovarian cancer patients, this study provides the rationale for establishing INPP4B as a biomarker of PARP inhibitor response, and consequently offers novel therapeutic options for a significant subset of patients. Loss of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) results in a DNA repair defect due to concomitant loss of BRCA1, ATR and ATM and can be therapeutically targeted with PARP inhibitors.
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影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
7.5
作者：
Downward, J
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影响因子：
50.3
作者：
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Cantley LC
影响因子：
16
作者：
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通讯作者：
Elledge SJ
影响因子：
4.3
作者：
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