靶向ATM-TRMT10A-BRCA1轴对PARP抑制转移性去势抵抗性前列腺癌具有合成致死性

IF 12.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Ying Yang, Qiang Liu, Xinyan Li, Hua Zhang, Xin Xu, Qi Ma, Somaira Nowsheen, Khaled Aziz, Ye-Xiong Li, Zhenkun Lou, Qiuzi Zhong, Min Deng
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引用次数: 0

摘要

转移性去势抵抗性前列腺癌(mCRPC)进展积极,抵抗现有治疗。尽管聚(adp -核糖)聚合酶抑制剂(PARPis)对一部分mCRPC和BRCA1/2缺陷患者有益,但对于没有这种突变的患者,治疗选择仍然有限。在这里,我们揭示了ATM-TRMT10A-BRCA1信号轴在调节同源重组(HR)修复和PARPi敏感性中的关键作用。我们证明了ATM在DNA损伤后磷酸化TRMT10A的丝氨酸-28位点,促进BRCA1的招募和有效的HR修复。TRMT10A缺失破坏HR修复,使细胞对parpi敏感。此外,TRMT10A通过USP10的稳定在mCRPC中上调。在细胞源性异种移植物和患者源性异种移植物模型中,用spautin-1靶向USP10诱导TRMT10A降解并增强肿瘤对PARPis的敏感性。这些发现确定了TRMT10A是mCRPC的治疗易感点,并证明联合抑制PARP和USP10为更广泛的缺乏经典BRCA突变的患者提供了一种有希望的合成致死策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting the ATM-TRMT10A-BRCA1 axis confers synthetic lethality to PARP inhibition in metastatic castration-resistant prostate cancer

Targeting the ATM-TRMT10A-BRCA1 axis confers synthetic lethality to PARP inhibition in metastatic castration-resistant prostate cancer
Metastatic castration-resistant prostate cancer (mCRPC) progresses aggressively and resists existing therapies. Although poly(ADP-ribose) polymerase inhibitors (PARPis) benefit a subset of patients with mCRPC and BRCA1/2 deficiencies, therapeutic options remain limited for those without such mutations. Here, we uncover a critical role for the ATM-TRMT10A-BRCA1 signaling axis in regulating homologous recombination (HR) repair and PARPi sensitivity. We demonstrate that ATM phosphorylates TRMT10A at serine-28 after DNA damage, promoting BRCA1 recruitment and efficient HR repair. TRMT10A deletion disrupts HR repair, sensitizing cells to PARPis. Moreover, TRMT10A is up-regulated in mCRPC through stabilization by USP10. Targeting USP10 with spautin-1 induces TRMT10A degradation and enhances tumor sensitivity to PARPis in cell-derived xenografts and patient-derived xenograft models. These findings identify TRMT10A as a therapeutic vulnerability in mCRPC and demonstrate that combined inhibition of PARP and USP10 offers a promising synthetic lethal strategy for a broader group of patients lacking classical BRCA mutations.
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来源期刊
Science Advances
Science Advances 综合性期刊-综合性期刊
CiteScore
21.40
自引率
1.50%
发文量
1937
审稿时长
29 weeks
期刊介绍: Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.
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