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.

中文翻译：

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阐明晚期前列腺癌的获得性 PARP 抑制剂耐药性


PARP 抑制 （PARPi） 对具有同源重组修复 （HRR） 缺陷的去势抵抗性前列腺癌 （CRPC） 具有抗肿瘤活性。然而，PARPi 耐药的潜在机制尚不完全清楚。虽然恢复 BRCA 基因的获得性突变有很好的文献记录，但其临床相关性、频率和产生机制仍不清楚。此外，BRCA2 纯合缺失 （HomDel） CRPC 中的耐药性是如何出现的尚不清楚。评估在 TOPARP-B 试验中接受治疗的转移性 CRPC 患者的样本，我们在治疗结束时确定了大多数 BRCA2/PALB2 突变肿瘤 （79%） 的逆转突变。在移码缺失介导的逆转中，60% 的侧翼是 DNA 微同源性，表明 POLQ 介导的修复。其检测的逆转次数和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 HomDels，在 PARPi 后观察到不含 BRCA2-HomDel 的稀有亚克隆的选择，通过单循环肿瘤细胞基因组学、活检荧光原位杂交 （FISH） 和 RNAish 证实。这些数据支持在 PARPi 抵抗中需要恢复 HRR 功能。