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. Significance: 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. See related commentary by Cai, [p. 2977][1] [1]: /lookup/volpage/80/2977?iss=14

中文翻译：

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脯氨酰异构酶Pin1的失活使BRCA1熟练的乳腺癌对PARP抑制敏感。

PARP抑制剂单一疗法可有效治疗患有BRCA1突变的乳腺癌，卵巢癌，前列腺癌和胰腺癌患者，但不适用于更常见的BRCA野生型癌症。在寻找将PARP抑制剂的应用扩展到BRCA1熟练肿瘤的策略中，我们发现电离辐射（IR）后BRCA1蛋白的稳定性通过脯氨酸异构酶Pin1催化的BRCA1的Ser1191附近的磷酸化脯氨酰异构化得以维持。 。Pin1的灭绝将同源重组（HR）降低至BRCA1缺陷细胞的水平。Pin1通过防止BRCA1的Lys1037泛素化来稳定BRCA1。Pin1的丢失，或引入对Pin1结合不耐的BRCA1突变体，会降低BRCA1定位修复灶的能力，并增加IR诱导的DNA损伤。使用全反式维甲酸（ATRA）的olaparib或Pin1抑制可适度抑制HR敏感的乳腺癌，前列腺癌和胰腺癌细胞的体外生长，而联合治疗可导致细胞增殖几乎完全阻断。在MDA-MB-231异种移植物和三阴性乳腺癌患者异种移植物中，Pin1或ATRA治疗的缺失都会降低BRCA1表达，并使乳腺肿瘤对olaparib敏感。总之，我们的研究表明，Pin1抑制与临床广泛使用的ATRA一起起有效的HR破坏作用，使BRCA1精通的肿瘤对PARP抑制敏感。意义：PARP抑制剂仅限于治疗同源重组缺陷型肿瘤。全反式维甲酸，通过抑制Pin1并使BRCA1不稳定，将PARP抑制剂的益处扩展到具有同源重组能力的肿瘤患者。见蔡的相关评论，[p。2977] [1] [1]：/ lookup / volpage / 80/2977？iss = 14