Department of Respiratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, PR China.
Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
Cell Death Dis. 2022 Oct 29;13(10):910. doi: 10.1038/s41419-022-05354-y.
Accumulating evidence supports evolutionary trait of drug resistance. Like resilience in other systems, most tumor cells experience drug-tolerant state before full resistance acquired. However, the underlying mechanism is still poorly understood. Here, we identify that EGF like domain multiple 7 (EGFL7) is a responsive gene to epidermal growth factor receptor (EGFR) kinase inhibition during a period when tumors are decimated. Moreover, our data reveal that the adaptive increase of EGFL7 during this process is controlled by the depression of nonsense-mediated mRNA decay (NMD) pathway. Upregulation of EGFL7 activates NOTCH signaling in lung cancer cells, which slows down the decrease of c-Myc caused by EGFR inhibition, thereby helping the survival of cancer cells. Our data, taken together, demonstrate that EGFL7 is a driver gene for resistance to EGFR kinase inhibition, and suggest that targeting EGFL7/NOTCH signaling may improve the clinical benefits of EGFR inhibitors in patients with EGFR mutant tumors.
越来越多的证据支持药物耐药性的进化特征。与其他系统的弹性一样，大多数肿瘤细胞在完全耐药之前都会经历药物耐受状态。然而，其潜在机制仍不清楚。在这里，我们发现表皮生长因子样域蛋白 7（EGFL7）是表皮生长因子受体（EGFR）激酶抑制期间对肿瘤大量减少有反应的基因。此外，我们的数据揭示了在这个过程中 EGFL7 的适应性增加是由无意义介导的 mRNA 降解（NMD）途径的抑制控制的。EGFL7 的上调激活了肺癌细胞中的 NOTCH 信号通路，从而减缓了 EGFR 抑制引起的 c-Myc 的减少，从而帮助癌细胞存活。我们的数据表明，EGFL7 是 EGFR 激酶抑制剂耐药的驱动基因，并表明靶向 EGFL7/NOTCH 信号通路可能提高 EGFR 抑制剂在 EGFR 突变肿瘤患者中的临床获益。
