Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, Colorado.
Mol Cancer Ther. 2022 Jan;21(1):48-57. doi: 10.1158/1535-7163.MCT-21-0098. Epub 2021 Nov 2.
Breast cancers that express hormonal receptors (HR) and HER2 display resistance to targeted therapy. Tumor-promotional signaling from the HER2 and estrogen receptor (ER) pathways converges at the cyclin D1 and cyclin-dependent kinases (CDK) 4 and 6 complex, which drives cell-cycle progression and development of therapeutic resistance. Therefore, we hypothesized that co-targeting of ER, HER2, and CDK4/6 may result in improved tumoricidal activity and suppress drug-resistant subclones that arise on therapy. We tested the activity of the triple targeted combination therapy with tucatinib (HER2 small-molecule inhibitor), palbociclib (CKD4/6 inhibitor), and fulvestrant (selective ER degrader) in HR/HER2 human breast tumor cell lines and xenograft models. In addition, we evaluated whether triple targeted combination prevents growth of tucatinib or palbociclib-resistant subclones Triple targeted combination significantly reduced HR/HER2 tumor cell viability, clonogenic survival, and growth. Moreover, survival of HR/HER2 cells that were resistant to the third drug in the regimen was reduced by the other two drugs in combination. We propose that a targeted triple combination approach will be clinically effective in the treatment of otherwise drug-resistant tumors, inducing robust responses in patients.
表达激素受体 (HR) 和人表皮生长因子受体 2 (HER2) 的乳腺癌对靶向治疗有耐药性。HER2 和雌激素受体 (ER) 通路的肿瘤促进信号在细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 (CDK) 4 和 6 复合物中汇聚，该复合物驱动细胞周期进程和治疗耐药性的发展。因此，我们假设 ER、HER2 和 CDK4/6 的共同靶向可能会导致杀伤肿瘤活性的提高，并抑制治疗过程中产生的耐药亚克隆。我们在 HR/HER2 人乳腺癌细胞系和异种移植模型中测试了曲妥珠单抗（HER2 小分子抑制剂）、哌柏西利（CDK4/6 抑制剂）和氟维司群（选择性 ER 降解剂）三重靶向联合治疗的活性。此外，我们评估了三重靶向联合治疗是否可以预防曲妥珠单抗或哌柏西利耐药亚克隆的生长。三重靶向联合显著降低了 HR/HER2 肿瘤细胞活力、集落形成存活和生长。此外，对方案中第三种药物耐药的 HR/HER2 细胞的存活被其他两种药物联合降低。我们提出，靶向三联治疗方法将在治疗其他耐药肿瘤方面具有临床疗效，可诱导患者产生强烈的反应。
