The Institute of Cancer Research, London, United Kingdom.
The Royal Marsden NHS Foundation Trust, London, United Kingdom.
J Clin Invest. 2024 Jun 4;134(21):e178278. doi: 10.1172/JCI178278.
BACKGROUNDClinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome, and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial.METHODSWhole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA-Seq (bulk and single nucleus), and IHC for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment.RESULTSShallow codeletion of RNASEH2B and adjacent RB1 - colocated at chromosome 13q14 - was common, deep codeletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant prostate cancer (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA-Seq indicated discordant loss of expression. IHC studies showed that loss of the 2 proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and posttreatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 WT tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicated RNASEH2B-loss tumor subclones.CONCLUSIONPARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss.TRIAL REGISTRATIONClinicaltrials.gov NCT01682772.FUNDINGAstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation.
临床试验表明，PARP 抑制剂的抗肿瘤活性超出了同源重组缺陷（HRD）的范围。RNASEH2B 缺失与 HRD 无关，并且在临床前对 PARP 抑制敏感。本研究报告了高级前列腺癌中 RNASEH2B 蛋白的丢失及其与 RB1 蛋白丢失、临床结局以及在 PARP 抑制治疗过程中的克隆动力学之间的关系，这是一项前瞻性临床试验。
使用全外显子组测序（WES）、RNA-Seq（批量和单个核）和 IHC 对来自多个高级前列腺癌患者队列的全肿瘤活检样本进行了检测，以检测 RNASEH2B 和 RB1。利用奥拉帕利治疗的 TOPARP-A 和 TOPARP-B 临床试验中的患者活检样本，评估了奥拉帕利治疗期间 RNASEH2B 克隆选择。
RNASEH2B 与相邻 RB1 的浅深度缺失（位于 13q14 染色体上）很常见，深度缺失则较为罕见，基因缺失与 mRNA 表达降低相关。在去势抵抗性前列腺癌（CRPC）活检中，RNASEH2B 和 RB1 的 mRNA 表达呈正相关，但单细胞 RNA-Seq 表明表达的不一致性缺失。免疫组化研究表明，这两种蛋白的丢失通常是独立发生的，这可能是由于随机的第二个等位基因丢失。来自 BRCA1/2 WT 肿瘤的预处理和转移性 CRPC（mCRPC）活检研究，在 TOPARP 二期试验中接受治疗，表明奥拉帕利根除了具有 RNASEH2B 缺失的肿瘤亚克隆。
PARP 抑制可能通过消除具有 RNASEH2B 缺失的肿瘤亚克隆，使患有 mCRPC 的男性受益。
Clinicaltrials.gov NCT01682772。
阿斯利康；英国癌症研究中心；医学研究理事会；英国癌症研究中心；英国前列腺癌协会；莫特基金会；前列腺癌基金会。
