Liang Jackson, Yao Xiaosai, Aouad Patrick, Wang Bu-Er, Crocker Lisa, Chaudhuri Subhra, Liang Yuxin, Darmanis Spyros, Giltnane Jennifer, Moore Heather M, Aimi Junko, Chang Ching-Wei, Gates Mary R, Eng-Wong Jennifer, Hafner Marc, Metcalfe Ciara
Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
Translational Medicine - Oncology, Genentech, South San Francisco, CA, USA.
Nat Cancer. 2025 Feb;6(2):357-371. doi: 10.1038/s43018-024-00898-8. Epub 2025 Jan 13.
Multiple next-generation molecules targeting estrogen receptor α (ERα) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance-associated mutations in ESR1 (encodes ERα). Here, we studied the impact of ERα antagonist/degraders against Esr1 mutations expressed in mouse mammary glands. Inhibition of mutant ERα induced mixed-lineage cells, characterized by aberrant co-engagement of normally disparate master transcription factors. Lineage infidelity was also observed in Esr1-wild-type mice upon long-term estrogen deprivation. In ER breast cancer biopsy specimens, heavily pretreated tumors with no ESR1 mutation detected (NMD) frequently exhibited mixed-lineage features. ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER breast cancer may underpin the differential benefit of investigational ERα therapeutics observed in ESR1-mutant versus NMD contexts.
多种靶向雌激素受体α（ERα）的新一代分子正在乳腺癌临床试验中接受研究，全球有数千名女性参与其中。这些分子的研发部分是受ESR1（编码ERα）中与耐药相关突变的发现所推动。在此，我们研究了ERα拮抗剂/降解剂对在小鼠乳腺中表达的Esr1突变的影响。对突变型ERα的抑制诱导了混合谱系细胞，其特征是正常情况下不同的主转录因子异常共同参与。在长期雌激素剥夺的Esr1野生型小鼠中也观察到了谱系不忠。在ER乳腺癌活检标本中，未检测到ESR1突变（NMD）的经过大量预处理的肿瘤经常表现出混合谱系特征。ESR1突变型肿瘤通常保留管腔特征和较高的ERα活性，并对ERα拮抗剂吉瑞司群表现出抗增殖反应。ESR1突变型肿瘤在治疗后获得了混合谱系特征。晚期ER乳腺癌中的谱系异质性可能是在ESR1突变与NMD情况下观察到的研究性ERα疗法的不同益处的基础。
