同源重组缺陷和半合子性驱动乳腺癌耐药，这一成果由美国纪念斯隆-凯特琳癌症中心Pedram Razavi小组经过不懈努力而取得。2026年3月4日出版的《自然》杂志发表了这项成果。

通过对5800多名患者的综合临床基因组学分析，该研究组发现种系(g)致病变异决定了获得性耐药的进化轨迹。研究小组特别发现，gBRCA2相关肿瘤独特地倾向于发展获得性RB1功能丧失改变，导致标准护理一线CDK4/6抑制剂（CDK4/6i）联合治疗的预后较差。这种脆弱性是由双重机制驱动的：基线RB1半合子性（杂合子丢失导致单个功能的RB1等位基因）降低了双等位基因失活的进化障碍，以及持续的同源基因重组缺陷，在CDK4/6i的选择压力下促进了RB1功能丧失改变的获得。

来自gBRCA2携带者的临床前模型显示出对CDK4/6i几乎一致的耐药性，治疗后Rb损失一致。在多个独立的模型和临床数据中，PARP抑制始终优于CDK4/6i。他们的研究结果表明，在gBRCA2携带者中优先抑制PARP可能会阻断RB1损失轨迹并延迟抗性。更广泛地说，课题组研究人员建立了一个基于治疗前等位基因配置和突变特征预测耐药轨迹的预测框架。

研究人员表示，在乳腺癌中经常观察到生殖系和体细胞致癌改变的共同发生，但它们对肿瘤进化和治疗耐药性的综合影响仍不清楚。

附：英文原文

Title: Homologous recombination deficiency and hemizygosity drive resistance in breast cancer

Author: Safonov, Anton, Lee, Minna, Brown, David N., Boscolo Bielo, Luca, Mehine, Miika, Bandlamudi, Chaitanya, OLeary, Ben, Shao, Hong, Vicente, Laia, Muldoon, Daniel, Zhu, Allen, Ros, Susana, Marra, Antonio, Selenica, Pier, Bieche, Ivan, Wubbenhorst, Bradley, Ferraro, Emanuela, Courtois, Laura, El Botty, Rania, Ahmed, Mehnaj, Moiso, Enrico, An, Julia Ah-Reum, Donoghue, Mark T. A., Will, Marie, Pareja, Fresia, Nizialek, Emily, Lukashchuk, Natalia, Sofianopoulou, Eleni, Liu, Yuan, Huang, Xin, Chappey, Colombe, Staniszewska, Anna D., Ross, Dara, Mandelker, Diana, Ladanyi, Marc, Schultz, Nikolaus, Berger, Michael F., Scaltriti, Maurizio, Reis-Filho, Jorge S., Li, Bob T., Offit, Kenneth, Norton, Larry, Shen, Ronglai, Maxwell, Kara N., Couch, Fergus, Domchek, Susan M., Marangoni, Elisabetta, Shah, Sohrab, Albertella, Mark R., Serra, Violeta, Weigelt, Britta, Solit, David B., Nathanson, Katherine L., Robson, Mark E., Turner, Nicholas C., Chandarlapaty, Sarat, Razavi, Pedram

Issue&Volume: 2026-03-04

Abstract: 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.

DOI: 10.1038/s41586-026-10197-0

Source: https://www.nature.com/articles/s41586-026-10197-0