The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
Breast Cancer Res. 2019 Mar 21;21(1):43. doi: 10.1186/s13058-019-1127-y.
The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.
Through a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model.
We now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models.
The interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance.
致癌受体酪氨酸激酶（RTK）ERBB2 已知通过与其他 EGFR 家族成员，特别是 ERBB3 形成二聚体，从而有力地激活 PI3K 信号通路。二十年来，抗体介导的抑制这种 ERBB2/ERBB3/PI3K 轴一直是 ERBB2 扩增型乳腺癌患者治疗的基石。然而，许多患者缺乏反应和快速复发，现在质疑了这些治疗方法认为 ERBB2/ERBB3 异二聚体是这些疗法唯一相关的效应靶标的假设。
通过系统的蛋白质-蛋白质相互作用筛选，我们已经鉴定并验证了与 ERBB2 相互作用的替代 RTKs。我们使用信号通路激活和细胞增殖的定量读数，研究了它们对曲妥珠单抗和帕妥珠单抗介导的 ERBB2 扩增型乳腺癌细胞系和患者衍生的异种移植模型中细胞生长抑制的作用机制。
我们现在证明，这些治疗性抗体对 ERBB3/PI3K 的失活不足以抑制 ERBB2 扩增型乳腺癌细胞的生长。相反，我们发现 ERBB2 与来自 EGFR 家族之外的一系列 RTKs 之间存在广泛的混杂性。矛盾的是，帕妥珠单抗也作为一种人工配体，通过一组非典型 RTKs 的变构激活来促进 ERBB2 的激活和 ERK 信号传导。然而，这种意外的激活机制也增加了受体网络对 ERBB2 激酶抑制剂拉帕替尼的敏感性，拉帕替尼与帕妥珠单抗联合使用，在单药耐药细胞系和 PDX 模型中显示出协同作用。
在接受帕妥珠单抗治疗后，ERBB2 与许多非典型 RTKs 的相互作用会激活代偿性信号反应，尽管 ERBB2 抗体治疗和激酶抑制剂的组合可以克服这种固有治疗耐药性。
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