Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition.
Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition.
复制标题
脯氨酰异构酶 Pin1 的失活使 BRCA1 丰富的乳腺癌对 PARP 抑制敏感。
DOI：
10.1158/0008-5472.can-19-2739
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发表时间：
2020-07-15
期刊：
影响因子：
11.2
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Luo ML;Zheng F;Chen W;Liang ZM;Chandramouly G;Tan J;Willis NA;Chen CH;Taveira MO;Zhou XZ;Lu KP;Scully R;Wulf GM;Hu H
PARP抑制剂单一疗法对BRCA1突变的乳腺癌、卵巢癌、前列腺癌和胰腺癌患者有效，但对更常见的BRCA野生型癌症无效。在寻找将PARP抑制剂应用于BRCA1富集肿瘤的策略时，我们发现BRCA1蛋白在电离辐射（IR）后的稳定性是由脯氨酸异构酶Pin1催化的BRCA1 Ser1191附近的磷酸化后脯氨酸异构化维持的。Pin1的消失使同源重组（HR）降低到brca1缺陷细胞的水平。Pin1通过阻止BRCA1的Lys1037泛素化来稳定BRCA1。Pin1缺失，或引入一种难以与Pin1结合的BRCA1突变体，会降低BRCA1定位修复病灶的能力，并增强ir诱导的DNA损伤。奥拉帕尼或使用全反式维甲酸（ATRA）抑制Pin1可适度抑制hrr精通的乳腺癌、前列腺癌和胰腺癌细胞的体外生长，而联合治疗可几乎完全阻断细胞增殖。在MDA-MB-231异种移植物和三阴性乳腺癌患者来源的异种移植物中，Pin1或ATRA治疗的缺失都降低了BRCA1的表达，并使乳腺肿瘤对奥拉帕尼敏感。总之，我们的研究表明，Pin1抑制与临床广泛使用的ATRA一起，作为一种有效的HR干扰物，使brca1精通的肿瘤对PARP抑制敏感。PARP抑制剂仅限于治疗同源重组缺陷肿瘤。全反式维甲酸通过抑制Pin1和破坏BRCA1的稳定，将PARP抑制剂的益处扩展到同源重组肿瘤患者。
PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition. PARP inhibitors have been limited to treat homologous recombination–deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination–proficient tumors.