Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer
Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer
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DOI：
10.1186/s13058-019-1127-y
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发表时间：
2019-03-21
影响因子：
7.4
通讯作者：
Croucher, David R.
中科院分区：
文献类型：
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作者：
Kennedy, Sean P.;Han, Jeremy Z. R.;Croucher, David R.
背景：已知致癌受体酪氨酸激酶 (RTK) ERBB2 与其他 EGFR 家族成员（特别是 ERBB3）形成二聚体，通过二聚体有效激活 PI3K 信号传导。二十年来，抗体介导的 ERBB2/ERBB3/PI3K 轴抑制一直是 ERBB2 扩增乳腺癌患者治疗的基石。然而，许多患者缺乏反应且快速复发，现在对 ERBB2/ERBB3 异二聚体是这些疗法的唯一相关效应靶点的假设提出质疑。 方法：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 RTK。使用信号通路激活和细胞增殖的定量读数，我们检查了它们对曲妥珠单抗和帕妥珠单抗介导的 ERBB2 扩增乳腺癌细胞系和患者来源的异种移植模型中细胞生长抑制机制的影响。结果：我们现在证明，这些治疗性抗体对 ERBB3/PI3K 的灭活不足以抑制 ERBB2 扩增乳腺癌细胞的生长。相反，我们发现 ERBB2 与 EGFR 家族之外的一系列 RTK 之间存在广泛的混杂性。矛盾的是，帕妥珠单抗还充当人工配体，通过这些非经典 RTK 的子集的变构激活来促进 ERBB2 激活和 ERK 信号传导。然而，这种意想不到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 模型中显示出协同效应。结论：ERBB2 与许多非经典 RTK 的相互作用在帕妥珠单抗治疗后激活了代偿性信号反应，尽管 ERBB2 抗体疗法和激酶抑制剂的反直觉组合可以克服这种先天性。治疗抵抗。
Background: 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.Methods: 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.Results: 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.Conclusions: 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.