Angus Steven P, Stuhlmiller Timothy J, Mehta Gaurav, Bevill Samantha M, Goulet Daniel R, Olivares-Quintero J Felix, East Michael P, Tanioka Maki, Zawistowski Jon S, Singh Darshan, Sciaky Noah, Chen Xin, He Xiaping, Rashid Naim U, Chollet-Hinton Lynn, Fan Cheng, Soloway Matthew G, Spears Patricia A, Jefferys Stuart, Parker Joel S, Gallagher Kristalyn K, Forero-Torres Andres, Krop Ian E, Thompson Alastair M, Murthy Rashmi, Gatza Michael L, Perou Charles M, Earp H Shelton, Carey Lisa A, Johnson Gary L
Department of Pharmacology, UNC Chapel Hill, Chapel Hill, NC, USA.
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
NPJ Breast Cancer. 2021 May 12;7(1):51. doi: 10.1038/s41523-021-00258-0.
Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.
抑制HER2/ERBB2受体是治疗HER2阳性恶性肿瘤（尤其是乳腺癌）的关键，但相当一部分HER2阳性（HER2+）乳腺癌会复发或无反应。抗HER2单克隆抗体（如曲妥珠单抗或帕妥珠单抗）以及ATP活性位点抑制剂（如拉帕替尼），由于肿瘤的适应性变化导致耐药，通常缺乏持久性。通过RNAseq和ChIPseq分析HER2+细胞系对拉帕替尼抑制的反应，以表征转录和表观遗传变化。对拉帕替尼反应性基因组区域的基序分析表明，先驱转录因子FOXA1是适应性反应的介导者。拉帕替尼与FOXA1缺失联合使用导致增强子失调、HER3适应性上调受损以及增殖减少。在一项为期7天的临床试验中，使用临床相关药物（曲妥珠单抗联合或不联合拉帕替尼或帕妥珠单抗）进行HER2导向治疗，以检查基于抗体的抗HER2治疗的早期药效学反应，结果显示FOXA1表达降低与HER2和HER3水平降低、增殖基因特征减少以及免疫基因特征增加同时出现。这突出了免疫反应对抗HER2抗体的重要性，并表明抑制FOXA1介导的适应性反应与靶向HER2相结合是一种潜在的治疗策略。
