奥拉帕尼
PALB2
PARP抑制剂
前列腺癌
癌症研究
损失函数
同源重组
合成致死
聚ADP核糖聚合酶
雷达51
突变
医学
癌症
内科学
生物
DNA修复
种系突变
遗传学
基因
表型
聚合酶
作者
Kasia M. Dillon,Raie T. Bekele,Zsófia Sztupinszki,Timothy Hanlon,Shahrzad Rafiei,Zoltán Szállási,Atish D. Choudhury,Kent W. Mouw
标识
DOI:10.1038/s41698-022-00291-7
摘要
Abstract PARP inhibitors were recently approved for treatment of molecularly-defined subsets of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP inhibitor olaparib was approved for use in patients with a mutation in one of fourteen genes, the mutation frequency of the genes varies widely in mCRPC and the impact of the less commonly altered genes on PARP inhibitor sensitivity is uncertain. We used functional approaches to directly test the impact of PALB2 and BARD1 loss on homologous recombination (HR) function and PARP inhibitor sensitivity in prostate cancer cell lines. PALB2 or BARD1 loss led to decreased HR function as measured by loss of radiation-induced Rad51 foci formation as well as decreased HR capacity in a cell-based reporter assay. PALB2 or BARD1 loss also significantly increased sensitivity to the PARP inhibitors olaparib and rucaparib across a panel of prostate cancer cell lines. These data support PALB2 and BARD1 loss as markers of clinically relevant PARP inhibitor sensitivity and highlight the potential to use functional approaches to complement and extend findings from clinical trials of targeted agents.
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