HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers
HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers
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ERBB2 扩增或突变肺癌中 HER2 介导的细胞毒性药物的内化
DOI：
10.1158/2159-8290.cd-20-0215
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发表时间：
2020-05-01
期刊：
影响因子：
28.2
通讯作者：
Scaltriti, Maurizio
中科院分区：
文献类型：
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作者：
Li, Bob T.;Michelini, Flavia;Scaltriti, Maurizio
编码HER2受体酪氨酸激酶的基因ERBB2的扩增和致癌突变促进受体过度激活和肿瘤生长。在这里，我们证明了HER2泛素化和内化，而不是它的过度表达，是导致内吞作用的关键机制，以及抗HER2抗体-药物结合物(ADC)ado-trastuzumab emtansine(T-DM1)和trastuzumab deruxtecan(T-DXd)在肺癌细胞系和患者来源的异种移植模型中的后续疗效。在49名ERBB2扩增或突变肺癌患者的T-DM1临床试验中，这些数据转化为51%的应答率。我们表明，与不可逆转的PAN-HER抑制剂共同治疗可增强受体泛素化，从而促进ADC的内化和有效性。我们还证明，在肺癌患者和相应的对T-DM1产生耐药性的异种移植模型中，ADC切换到T-DXd可以获得持久的反应，因为T-DXd含有不同的细胞毒性有效载荷。我们的发现可能有助于指导未来的临床试验，并扩大ADC作为癌症治疗的领域。迹象：T-DM1对ERBB2扩增或突变的肺癌临床有效。这种活性通过与不可逆的PAN-HER抑制剂或ADC切换到T-DXd共同处理而增强。这些结果可能有助于解决HER2激活的肿瘤患者未得到满足的需求，并且没有获得批准的靶向治疗。
Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.