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.

PARP 抑制剂最近被批准用于治疗分子定义的转移性去势抵抗性前列腺癌 (mCRPC) 患者亚群。尽管 PARP 抑制剂 olaparib 被批准用于 14 个基因之一发生突变的患者，但 mCRPC 中基因的突变频率差异很大，并且不太常见的改变基因对 PARP 抑制剂敏感性的影响尚不确定。我们使用功能方法直接测试 PALB2 和 BARD1 缺失对前列腺癌细胞系同源重组 (HR) 功能和 PARP 抑制剂敏感性的影响。PALB2 或 BARD1 损失导致 HR 功能下降，这是通过辐射诱导的 Rad51 病灶形成的损失以及基于细胞的报告基因检测中 HR 能力下降来衡量的。PALB2 或 BARD1 缺失还显着增加了一组前列腺癌细胞系对 PARP 抑制剂 olaparib 和 rucaparib 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物，并强调了使用功能性方法来补充和扩展靶向药物临床试验结果的潜力。