Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation.
Tingting LiaoJingjing DengWenjuan ChenJuanjuan XuGuanghai YangMei ZhouZhilei LvSufei WangSiwei SongXueyun TanZhengrong YinYumei LiYang JinPublished in: Cancers (2022)
Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells.
Keyphrases
- small cell lung cancer
- epidermal growth factor receptor
- cell cycle arrest
- induced apoptosis
- advanced non small cell lung cancer
- endoplasmic reticulum stress
- cell death
- tyrosine kinase
- pi k akt
- oxidative stress
- signaling pathway
- brain metastases
- rna seq
- transcription factor
- skeletal muscle
- copy number
- gene expression
- reactive oxygen species
- combination therapy
- genome wide
- replacement therapy
- wild type