Department of Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research, Johns Hopkins University, Baltimore, Maryland, USA.
PLoS One. 2013 Jul 31;8(7):e68966. doi: 10.1371/journal.pone.0068966. Print 2013.
The sensitivity of only a few tumors to anti-epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations. In addition, such mutations were rarely found in tumor types other than lung, such as pancreatic and head and neck cancer. In this study we sought to elucidate mechanisms of resistance to EGFR-targeted therapies in tumors that do not harbor TK sensitizing mutations in order to identify markers capable of guiding the decision to incorporate these drugs into chemotherapeutic regimens. Here we show that EGFR activity was markedly decreased during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib, with a concomitant increase of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR through the upregulation of the PI3K-AKT pathway. EGFR activity, which was more accurately predicted by the ratio of Mig6/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. Blinded testing and analysis in a prospectively followed cohort of lung cancer patients treated with gefitinib alone demonstrated higher response rates and a marked increased in progression free survival for patients with a low Mig6/EGFR ratio (approximately 100 days, P = 0.01).
只有少数肿瘤对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）敏感，这可以用 EGFR 酪氨酸激酶（TK）结构域突变来解释。此外，这种突变在非肺部肿瘤类型中很少见，如胰腺癌和头颈部癌症。在这项研究中，我们试图阐明在不携带 TK 敏感突变的肿瘤中对 EGFR 靶向治疗产生耐药的机制，以确定能够指导将这些药物纳入化疗方案的标志物。在这里，我们发现 EGFR 活性在对 EGFR 酪氨酸激酶抑制剂（TKI）厄洛替尼产生耐药性的过程中明显降低，同时原肌球蛋白诱导基因 6（Mig6）增加，Mig6 通过上调 PI3K-AKT 通路成为 EGFR 的负调控因子。EGFR 活性更准确地由 Mig6/EGFR 的比值预测，该比值与不同组织来源的癌细胞系中厄洛替尼敏感性高度相关。在接受吉非替尼单独治疗的前瞻性随访肺癌患者队列中进行的盲法检测和分析表明，Mig6/EGFR 比值较低的患者的反应率更高，无进展生存期明显延长（约 100 天，P = 0.01）。
