Sinevici Nicoleta, Ataeinia Bahar, Zehnder Veronica, Lin Kevin, Grove Lauren, Heidari Pedram, Mahmood Umar
Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
Front Oncol. 2020 Nov 20;10:554704. doi: 10.3389/fonc.2020.554704. eCollection 2020.
Triple Negative Breast Cancer (TNBC) is an aggressive form of Breast Cancer (BC). Numerous kinase inhibitors (KI) targeting different pathway nodes have shown limited benefit in the clinical setting. In this study, we aim to characterize the extent of HER3 reliance and to define the effect of Neuregulin (NRG) isoforms in TNBCs. Basal and Claudin type TNBC cell lines were treated with a range of small molecule inhibitors, in the presence or absence of the HER3 ligand NRG. Single agent and combination therapy was also evaluated in human cancer cell lines through viability and biochemical assessment of the AKT/MAPK signaling pathway. We show that Basal (BT20, HCC-70, and MDA-MB-468) and Claudin type (MDA-MB-231, BT-549) TNBC cell lines displayed differential reliance on the HER family of receptors. Expression and dynamic HER3 upregulation was predominant in the Basal TNBC subtype. Furthermore, the presence of the natural ligand NRG showed potent signaling through the HER3-AKT pathway, significantly diminishing the efficacy of the AKT and PI3K inhibitors tested. We report that NRG augments the HER3 feedback mechanism for continued cell survival in TNBC. We demonstrate that combination strategies to effectively block the EGFR-HER3-AKT pathway are necessary to overcome compensatory mechanisms to NRG dependent and independent resistance mechanisms. Our findings suggests that the EGFR-HER3 heterodimer forms a major signaling hub and is a key player in tumorigenesis in Basal but not Claudin type TNBC tested. Thus, HER3 could potentially serve as a biomarker for identifying patients in which targeted therapy against the EGFR-HER3-AKT axis would be most valuable.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌（BC）。众多靶向不同信号通路节点的激酶抑制剂（KI）在临床应用中显示出有限的疗效。在本研究中，我们旨在明确HER3依赖性的程度，并确定神经调节蛋白（NRG）亚型在TNBC中的作用。在存在或不存在HER3配体NRG的情况下，用一系列小分子抑制剂处理基底样和Claudin型TNBC细胞系。还通过对AKT/MAPK信号通路的活力和生化评估，在人癌细胞系中评估了单药治疗和联合治疗。我们发现，基底样（BT20、HCC-70和MDA-MB-468）和Claudin型（MDA-MB-231、BT-549）TNBC细胞系对HER家族受体表现出不同的依赖性。HER3的表达和动态上调在基底样TNBC亚型中占主导地位。此外，天然配体NRG的存在通过HER3-AKT途径显示出强大的信号传导，显著降低了所测试的AKT和PI3K抑制剂的疗效。我们报告称，NRG增强了HER3反馈机制，以维持TNBC中的细胞存活。我们证明，有效阻断EGFR-HER3-AKT途径的联合策略对于克服对NRG依赖性和非依赖性耐药机制的补偿机制是必要的。我们的研究结果表明，EGFR-HER3异二聚体形成了一个主要的信号枢纽，并且是所测试的基底样而非Claudin型TNBC肿瘤发生中的关键参与者。因此，HER3有可能作为一种生物标志物，用于识别针对EGFR-HER3-AKT轴的靶向治疗最有价值的患者。
