文章：

同源重组缺陷和半合子状态驱动乳腺癌耐药性

Homologous recombination deficiency and hemizygosity drive resistance in breast cancer

原文发布日期：2026-03-04

DOI: 10.1038/s41586-026-10197-0

类型: Article

开放获取: 是

英文摘要：

The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, yet their combined influence on tumour evolution and therapy resistance remains poorly defined. Through an integrated clinicogenomic analysis of more than 5,800 patients, we show that germline (g) pathogenic variants dictate the evolutionary trajectory of acquired resistance. We specifically find that gBRCA2-associated tumours are uniquely predisposed to develop acquired RB1 loss-of-function alterations, resulting in poor outcomes on standard-of-care frontline CDK4/6 inhibitor (CDK4/6i) combinations. This vulnerability is driven by a dual mechanism: baseline RB1 hemizygosity (heterozygous loss resulting in a single functional RB1 allele), which lowers the evolutionary barrier to biallelic inactivation, and ongoing homologous recombination deficiency, which promotes acquisition of RB1 loss-of-function alterations under the selective pressure of CDK4/6i. Preclinical models from gBRCA2 carriers showed near-uniform resistance to CDK4/6i, with consistent post-treatment Rb loss. Across multiple independent models and in our clinical data, PARP inhibition consistently outperformed CDK4/6i. Our findings suggest that prioritizing PARP inhibition in gBRCA2 carriers may intercept RB1-loss trajectories and delay resistance. More broadly, we establish a predictive framework for forecasting drug-resistant trajectories based on pre-treatment allelic configuration and mutational signatures.

摘要翻译： 

在乳腺癌中，胚系和体细胞致癌性改变常同时发生，但二者对肿瘤进化和治疗耐药性的综合影响仍不明确。通过对5800余名患者进行临床基因组学整合分析，我们发现胚系致病性变异决定了获得性耐药的进化轨迹。具体而言，我们确认携带胚系BRCA2突变的肿瘤具有独特的易感性，更易发生获得性RB1功能丧失性改变，导致标准一线CDK4/6抑制剂联合治疗疗效不佳。这种脆弱性源于双重机制：基线水平的RB1半合子状态（杂合性缺失导致仅存单个功能性RB1等位基因）降低了双等位基因失活的进化屏障，而持续存在的同源重组缺陷则促使在CDK4/6抑制剂选择性压力下获得RB1功能丧失性改变。来自胚系BRCA2携带者的临床前模型显示，几乎所有模型均对CDK4/6抑制剂产生耐药，且治疗后持续出现Rb蛋白缺失。在多个独立模型及临床数据中，PARP抑制剂的疗效始终优于CDK4/6抑制剂。我们的研究结果表明，对胚系BRCA2携带者优先采用PARP抑制剂治疗可能阻断RB1缺失的进化路径并延缓耐药产生。更广泛而言，我们建立了基于治疗前等位基因构型及突变特征的耐药轨迹预测框架。

原文链接：

Homologous recombination deficiency and hemizygosity drive resistance in breast cancer