PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer.
PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer.
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DOI：
10.1038/s41698-022-00291-7
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发表时间：
2022-06-29
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
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作者：
PARP抑制剂最近被批准用于治疗转移性去势抵抗性前列腺癌（mCRPC）患者的分子定义亚群。尽管PARP抑制剂奥拉帕尼被批准用于14个基因突变之一的患者，但mCRPC中这些基因的突变频率差异很大，而且不太常见的突变基因对PARP抑制剂敏感性的影响尚不确定。我们采用功能方法直接检测PALB2和BARD1缺失对前列腺癌细胞同源重组（HR）功能和PARP抑制剂敏感性的影响。PALB2或BARD1的缺失导致HR功能下降，这可以通过辐射诱导的Rad51病灶形成的缺失来测量，也可以通过基于细胞的报告实验来测量HR容量的下降。在一组前列腺癌细胞系中，PALB2或BARD1缺失也显著增加了对PARP抑制剂奥拉帕尼和鲁卡帕尼的敏感性。这些数据支持PALB2和BARD1缺失作为临床相关PARP抑制剂敏感性的标志，并强调了使用功能方法补充和扩展靶向药物临床试验结果的潜力。
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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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
7.2
作者：
Prakash R;Zhang Y;Feng W;Jasin M
通讯作者：
Jasin M
影响因子：
28.2
作者：
Carreira, Suzanne;Porta, Nuria;Arce-Gallego, Sara;Seed, George;Llop-Guevara, Alba;Bianchini, Diletta;Rescigno, Pasquale;Paschalis, Alec;Bertan, Claudia;Baker, Chloe;Goodall, Jane;Miranda, Susana;Riisnaes, Ruth;Figueiredo, Ines;Ferreira, Ana;Pereira, Rita;Crespo, Mateus;Gurel, Bora;Rodrigues, Daniel Nava;Pettitt, Stephen J.;Yuan, Wei;Serra, Violeta;Rekowski, Jan;Lord, Christopher J.;Hall, Emma;Mateo, Joaquin;de Bono, Johann S.
通讯作者：
de Bono, Johann S.
影响因子：
12.3
作者：
Poti, Adam;Gyergyak, Hella;Szuets, David
通讯作者：
Szuets, David
影响因子：
45.3
作者：
Reiss, Kim A.;Mick, Rosemarie;Domchek, Susan M.
通讯作者：
Domchek, Susan M.