解析晚期前列腺癌中获得性聚（ADP-核糖）聚合酶（PARP）抑制剂耐药性
Elucidating acquired PARP inhibitor resistance in advanced prostate cancer.
作者信息
Seed George, Beije Nick, Yuan Wei, Bertan Claudia, Goodall Jane, Lundberg Arian, Tyler Matthew, Figueiredo Ines, Pereira Rita, Baker Chloe, Bogdan Denisa, Gallagher Lewis, Cieslik Jan-Phillipp, Greening Semini, Lambros Maryou, Neves Rui, Magraner-Pardo Lorena, Fowler Gemma, Ebbs Berni, Miranda Susana, Flohr Penny, Bianchini Diletta, Rescigno Pasquale, Porta Nuria, Hall Emma, Gurel Bora, Tunariu Nina, Sharp Adam, Pettit Stephen, Stoecklein Nikolas H, Sandhu Shahneen, Quigley David, Lord Christopher J, Mateo Joaquin, Carreira Suzanne, de Bono Johann
机构信息
The Institute of Cancer Research, London, UK.
The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.
出版信息
Cancer Cell. 2024 Dec 9;42(12):2113-2123.e4. doi: 10.1016/j.ccell.2024.10.015. Epub 2024 Nov 21.
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.
聚（ADP-核糖）聚合酶抑制（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耐药的潜在机制尚未完全明确。虽然恢复BRCA基因的获得性突变已有充分记录，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）的CRPC中耐药如何出现尚不清楚。通过评估TOPARP-B试验中接受治疗的转移性CRPC患者的样本，我们发现在治疗结束时，大多数BRCA2/PALB2突变肿瘤（79%）中存在回复突变。在由移码缺失介导的回复突变中，60%侧翼为DNA微同源性，提示由POLQ介导的修复。回复突变的数量及其检测时间与无放射学进展生存期和总生存期相关（p<0.01）。对于BRCA2 HomDel，PARPi治疗后观察到对无BRCA2-HomDel的罕见亚克隆的选择，这通过单细胞循环肿瘤细胞基因组学、活检荧光原位杂交（FISH）和RNA原位杂交得以证实。这些数据支持在PARPi耐药中恢复HRR功能的必要性。
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