对于 ER 转移性乳腺癌 (mBC) 患者，一线治疗包括内分泌治疗 (ET) 和 CDK4/6 抑制剂 (CDK4/6i) 的联合治疗。然而，相当多的患者会经历疾病进展，这强调了临床迫切需要确定新型抗肿瘤疗法。我们之前从 MCF7 和 T47D（MCF7-FAR 和 T47D-FAR）中产生了对氟维司群（ER 下调剂）和 abemaciclib（CDK4/6 抑制剂）组合具有耐药性的乳腺癌细胞。基于 RNA 序列的基因集富集分析 (GSEA) 揭示了 MCF7-FAR 和 T47D-FAR 中 EGFR、HER2 和 AKT 信号传导的过度激活。通过功能丧失和功能获得实验调节 EGFR 或 ERBB2 表达，改变了亲本和 FAR 球体中肿瘤对氟维司群和 abemaciclib 的敏感性，影响 ERK 和 AKT/S6 通路。西妥昔单抗治疗克服了 FAR 和 EGFR 过表达乳腺癌球体和异种移植物中肿瘤对氟维司群和 abemaciclib 的耐药性。同样，来自 ER mBC 患者的患者源性类器官 (PDO) 在接受 Palbociclib 治疗后进展，表现出 EGFR 和 HER2 通路的上调。总之，我们的研究结果表明，抑制 EGFR 和 HER2 通路可能会克服选定的 ER mBC 患者对 ET CDK4/6i 的耐药性。版权所有 © 2024。由 Elsevier B.V 出版。

In patients with ER+ metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). However, a significant group of patients experiences disease progression, emphasizing the urgent clinical need to identify novel anti-tumor therapies. We previously generated breast cancer cells resistant to the combination of fulvestrant (ER downregulator) and abemaciclib (CDK4/6 inhibitor) from MCF7 and T47D (MCF7-FAR and T47D-FAR). RNA-seq-based Gene Set Enrichment Analysis (GSEA) revealed hyper-activation of EGFR, HER2, and AKT signaling in both MCF7-FAR and T47D-FAR. Modulating EGFR or ERBB2 expression through loss- and gain-of-function experiments altered tumor sensitivity to fulvestrant and abemaciclib in parental and FAR spheroids, affecting ERK and AKT/S6 pathways. Cetuximab treatment overcame tumor resistance to fulvestrant and abemaciclib in FAR and EGFR-overexpressing breast cancer spheroids and xenografts. Likewise, patient-derived organoids (PDOs) from individuals with ER+ mBC, progressing on palbociclib, exhibited up-regulation of EGFR and HER2 pathways. In conclusion, our findings suggest that inhibiting EGFR and HER2 pathways might overcome resistance to ET+CDK4/6i in selected patients with ER+ mBC.Copyright © 2024. Published by Elsevier B.V.