IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer
IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer
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DOI：
10.1158/1541-7786.mcr-19-0956
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发表时间：
2020-04-01
影响因子：
5.2
通讯作者：
Soejima, Kenzo
中科院分区：
文献类型：
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作者：
Manabe, Tadashi;Yasuda, Hiroyuki;Soejima, Kenzo
EGFR突变型肺癌占全球肺癌病例的很大比例。对于这些病例，第三代EGFR酪氨酸激酶抑制剂奥希替尼被广泛用作一线或二线治疗。然而，肺癌细胞在1至2年内获得对奥希替尼的耐药性。因此，对奥希替尼耐药机制的彻底澄清是高度期待的。最近肺癌样本的下一代测序（NGS）确定了几种基因定义的奥希替尼耐药机制，如EGFR C797S或MET扩增。然而，非遗传定义的机制没有得到很好的评价。为了彻底阐明奥希替尼耐药，遗传和非遗传机制都是必不可少的。通过使用我们的综合蛋白磷酸化阵列，我们检测了EGFR消除后IGF1R旁路途径的激活。我们建立的肺癌细胞和患者来源的肺癌细胞均显示IGF2自分泌介导的IGF1R途径激活是奥希替尼耐药的机制。值得注意的是，这种耐药机制没有被先前进行的NGS检测到，这突出了活癌细胞对于彻底阐明耐药机制的重要作用。有趣的是，免疫组织化学分析证实了接受奥希替尼治疗的肺癌患者中IGF 2表达增加，并符合获得性耐药的既定临床定义。这些发现强调了细胞自主配体表达在奥希替尼耐药中的关键作用。在此，我们首次报道了IGF 2自分泌介导的IGF 1R活化作为临床相关水平的肺癌奥希替尼耐药的非遗传机制。
EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level.