Li Lanxin, Liu Chenyang, Wang Rui, Yang Xiaolin, Wei Xiangkai, Chu Chunhong, Zhang Guoliang, Liu Chenxue, Cui Wenrui, Xu Huixia, Wang Ke, An Lei, Li Xiaodong
No.115, Ximen Avenue, Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, 475000, China.
Institute of Metabolism and Health, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
Sci Rep. 2024 Oct 2;14(1):22895. doi: 10.1038/s41598-024-73293-z.
Mutations in the epidermal growth factor receptor (EGFR) gene are common driver oncogenes in non-small cell lung cancer (NSCLC). Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the G719X (G719A, G719C and G719S) mutation has not been fully established. Herein, using the CRISPR method, the EGFR G719X mutant cell lines were constructed to assess the sensitivity of the rare mutation G719X in NSCLC. WZ3146, a novel mutation-selective EGFR inhibitor, was conducted transcriptome sequencing and in vitro experiments. The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.
表皮生长因子受体（EGFR）基因的突变是非小细胞肺癌（NSCLC）中常见的驱动癌基因。研究表明，阿法替尼对具有罕见EGFR突变的NSCLC患者有益。然而，酪氨酸激酶抑制剂（TKIs）针对G719X（G719A、G719C和G719S）突变的有效性尚未完全确立。在此，利用CRISPR方法构建了EGFR G719X突变细胞系，以评估NSCLC中罕见突变G719X的敏感性。对新型突变选择性EGFR抑制剂WZ3146进行了转录组测序和体外实验。结果表明，WZ3146在EGFR G719X突变细胞中诱导细胞毒性作用，通过ERK和AKT途径抑制生长活力和增殖。我们的研究结果表明，WZ3146可能是EGFR外显子18替代突变G719X的NSCLC患者的一种有前景的治疗选择。
