PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy.
PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy.
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PTEN 缺陷使子宫内膜样子宫内膜癌对复合 PARP-PI3K 抑制敏感，但对 PARP 抑制作为单一疗法不敏感
DOI：
10.1038/onc.2017.326
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发表时间：
2018-01-18
期刊：
影响因子：
8
通讯作者：
Cheng H
中科院分区：
文献类型：
--
作者：
Bian X;Gao J;Luo F;Rui C;Zheng T;Wang D;Wang Y;Roberts TM;Liu P;Zhao JJ;Cheng H
聚（ADP-核糖）聚合酶（PARP）抑制剂已成为有前途的癌症治疗剂，特别是对于同源重组（HR）修复缺陷的肿瘤。然而，由于HR缺陷型肿瘤仅占子宫内膜癌的一小部分，因此PARP抑制剂在这种疾病中的治疗效用有限。磷酸酶和张力蛋白同源物（PTEN）的体细胞丢失是类子宫内膜癌中最常见的遗传畸变之一，PTEN是一种抑制磷酸肌醇3-激酶（PI 3 K）活性的肿瘤抑制因子。虽然以前的工作已经确定了PTEN在DNA双链断裂修复中的作用，但PTEN缺陷的类子宫内膜癌对PARP抑制的脆弱性仍然存在争议。在这里，我们发现PTEN缺陷的子宫内膜样子宫内膜癌细胞对单独的PARP抑制剂奥拉帕尼没有反应，而是对PI 3 K抑制剂BKM 120的化合物抑制表现出上级敏感性，正如克隆源性细胞生长减少和三维（3D）球体崩解所证明的那样。从机制上讲，BKM 120阻断PI 3 K可减弱HR对γ H2 AX蓄积的能力，并降低石川、AN 3CA和Nou-1细胞中的RAD 51和BRCA 1表达，但相同的联合治疗可增强Hec-108细胞中DNA-PK（一种非同源末端连接修复蛋白）的磷酸化。此外，我们表明，CRISPR/Cas9介导的PTEN缺失使PTEN野生型Hec-1A类凋亡性子宫内膜癌细胞对PARP/PI 3 K的联合抑制有反应，同时诱导DNA损伤积累和修复缺陷。BKM 120和奥拉帕尼的组合在Pten缺陷的类胶质子宫内膜癌的遗传小鼠模型中协同抑制肿瘤生长。总之，这些结果表明，PI 3 K抑制可能是一种合理的方法，以扩大PARP抑制剂的效用，在PTEN缺陷的情况下，子宫内膜癌。
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising cancer therapeutics especially for tumors with deficient homologous recombination (HR) repair. However, as HR-deficient tumors represent only a small fraction of endometrial cancers, the therapeutic utility of PARP inhibitors is limited in this disease. Somatic loss of phosphatase and tensin homolog (PTEN), a tumor suppressor that counteracts phosphoinositide 3-kinase (PI3K) activity, is one of the most common genetic aberrations in endometrioid endometrial cancer. While previous works have identified the role of PTEN in DNA double-strand break repair, vulnerabilities of PTEN-deficient endometrioid endometrial cancers to PARP inhibition remain controversial. Here we find that PTEN-deficient endometrioid endometrial cancer cells are not responsive to PARP inhibitor Olaparib alone, but instead show superior sensitivity to compound inhibition with PI3K inhibitor BKM120, as evidenced by reduced clonogenic cell growth and three-dimensional (3D) spheroid disintegration. Mechanistically, PI3K blockade by BKM120 attenuated HR competency with γH2AX accumulation and reduced RAD51 and BRCA1 expression in Ishikawa, AN3CA and Nou-1 cells, but the same combination treatment led to enhanced phosphorylation of DNA-PK, a non-homologous end joining repair protein, in Hec-108 cells. Furthermore, we show that CRISPR/Cas9-mediated PTEN depletion rendered PTEN wild-type Hec-1A endometrioid endometrial cancer cells responsive to combined inhibition of PARP/PI3K, with concomitantly induced DNA damage accumulation and repair defects. The combination of BKM120 and Olaparib cooperated to inhibit tumor growth in a genetic mouse model of Pten-deficient endometrioid endometrial cancer. Together, these results suggest PI3K inhibition may be a plausible approach to expand the utility of PARP inhibitors to endometrioid endometrial cancers in a PTEN-deficient setting.
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