英国伦敦癌症研究所Johann de Bono团队近期取得重要工作进展，他们研究了晚期前列腺癌获得性PARP抑制剂耐药的机理。相关研究成果2024年11月21日在线发表于《癌细胞》杂志上。

据介绍，PARP抑制（PARPi）对具有同源重组修复（HRR）缺陷的去势耐受性癌症（CRPC）具有抗肿瘤活性。然而，PARPi抗性的机制尚未完全清楚。虽然恢复BRCA基因的获得性突变有很好的记录，但它们的临床相关性、频率和产生机制尚不清楚。此外，BRCA2纯合缺失（HomDel）CRPC中抗性是如何出现的尚不清楚。

通过评估TOPARP-B试验中治疗的转移性CRPC患者的样本，研究人员在治疗结束时发现了大多数BRCA2/PALB2突变肿瘤（79%）的逆转突变。在由移码缺失介导的逆转中，60%的逆转两侧有DNA微同源性，这意味着POLQ介导的修复。

逆转次数和检测时间与放射学无进展生存期和总生存期相关（p < 0.01）。对于BRCA2 HomDel，在PARPi后观察到不含BRCA2 HomDel的罕见亚克隆的选择，并通过单循环肿瘤细胞基因组学、活检荧光原位杂交（FISH）和RNAish得到证实。

总之，这一研究支持在PARPi耐受中需要恢复HRR的功能。

附：英文原文

Title: Elucidating acquired PARP inhibitor resistance in advanced prostate cancer

Author: George Seed, Nick Beije, Wei Yuan, Claudia Bertan, Jane Goodall, Arian Lundberg, Matthew Tyler, Ines Figueiredo, Rita Pereira, Chloe Baker, Denisa Bogdan, Lewis Gallagher, Jan-Phillipp Cieslik, Semini Greening, Maryou Lambros, Rui Neves, Lorena Magraner-Pardo, Gemma Fowler, Berni Ebbs, Susana Miranda, Penny Flohr, Diletta Bianchini, Pasquale Rescigno, Nuria Porta, Emma Hall, Bora Gurel, Nina Tunariu, Adam Sharp, Stephen Pettit, Nikolas H. Stoecklein, Shahneen Sandhu, David Quigley, Christopher J. Lord, Joaquin Mateo, Suzanne Carreira, Johann de Bono

Issue&Volume: 2024-11-21

Abstract: PARP inhibition (PARPi) has anti-tumor activity against castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) defects. However, mechanisms underlying PARPi resistance are not fully understood. While acquired mutations restoring BRCA genes are well documented, their clinical relevance, frequency, and mechanism of generation remain unclear. Moreover, how resistance emerges in BRCA2 homozygously deleted (HomDel) CRPC is unknown. Evaluating samples from patients with metastatic CRPC treated in the TOPARP-B trial, we identify reversion mutations in most BRCA2/PALB2-mutated tumors (79%) by end of treatment. Among reversions mediated by frameshift deletions, 60% are flanked by DNA microhomologies, implicating POLQ-mediated repair. The number of reversions and time of their detection associate with radiological progression-free survival and overall survival (p < 0.01). For BRCA2 HomDels, selection for rare subclones without BRCA2-HomDel is observed following PARPi, confirmed by single circulating-tumor-cell genomics, biopsy fluorescence in situ hybridization (FISH), and RNAish. These data support the need for restored HRR function in PARPi resistance.

DOI: 10.1016/j.ccell.2024.10.015

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00403-3