双重靶向 MEK 和 PI3K 可有效控制具有不同遗传背景的人表皮生长因子受体酪氨酸激酶抑制剂耐药非小细胞肺癌细胞系的增殖。

Dual targeting of MEK and PI3K effectively controls the proliferation of human EGFR-TKI resistant non-small cell lung carcinoma cell lines with different genetic backgrounds.

机构信息

Department of Respiratory and Critical Care Medicine, Second Medical Center of Chinese PLA General Hospital, No. 28 of Fuxing Street, Haidian District, Beijing, 100853, China.

Department of Laboratory Diagnosis, Second Medical Center of Chinese, PLA General Hospital, Beijing, 100853, China.

出版信息

BMC Pulm Med. 2021 Jul 1;21(1):208. doi: 10.1186/s12890-021-01571-x.

BACKGROUND

Molecular targeted therapy for non-small cell lung carcinoma (NSCLC) is restricted due to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This study evaluated the effects of dual targeting of MEK and PI3K in human EGFR-TKI resistant NSCLC cell lines.

METHODS

EGFR-TKI resistant NSCLC cell lines H1975, H460, and A549, with different mutation and amplification status in EGFR, K-RAS, PIK3CA, and MET genes, were treated with a MEK162 (MEK inhibitor) and BKM120 (PI3K inhibitor) combination or a BIBW2992 (EGFR inhibitor) and ARQ197 (MET inhibitor) combination and assayed for cell proliferation, apoptosis, and cell cycle distribution.

RESULTS

Dual targeting of MEK and PI3K efficiently inhibited the cell proliferation, induced apoptosis and the G0/G1 cell cycle, and decreased the phosphorylation of ERK1/2, AKT, S6, and 4E-BP1. H460 cells with K-RAS and PIK3CA mutation were most sensitive to MEK162 and BKM120 combinations. H1975 cells with EGFR and PIK3CA mutation and MET amplification were sensitive to BIBW2992 and ARQ197 combinations.

CONCLUSION

Dual targeting regulated the proliferation of EGFR-TKI-resistant NSCLC cells, especially mutants in K-RAS and PIK3CA that are promising for EGFR-TKI-resistant NSCLC therapeutics.

背景

非小细胞肺癌（NSCLC）的分子靶向治疗受到表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）耐药性的限制。本研究评估了双重 MEK 和 PI3K 靶向在人类 EGFR-TKI 耐药 NSCLC 细胞系中的作用。

方法

用 MEK162（MEK 抑制剂）和 BKM120（PI3K 抑制剂）联合或 BIBW2992（EGFR 抑制剂）和 ARQ197（MET 抑制剂）联合处理具有不同 EGFR、K-RAS、PIK3CA 和 MET 基因突变和扩增状态的 EGFR-TKI 耐药 NSCLC 细胞系 H1975、H460 和 A549，检测细胞增殖、凋亡和细胞周期分布。

结果

双重 MEK 和 PI3K 靶向有效地抑制了细胞增殖，诱导了细胞凋亡和 G0/G1 细胞周期，并降低了 ERK1/2、AKT、S6 和 4E-BP1 的磷酸化。具有 K-RAS 和 PIK3CA 突变的 H460 细胞对 MEK162 和 BKM120 联合最为敏感。具有 EGFR 和 PIK3CA 突变和 MET 扩增的 H1975 细胞对 BIBW2992 和 ARQ197 联合敏感。