LAUSR

Simple Summary The anti-tumor role of Fasudil in EGFR-mutation NSCLC as well as its mechanism are largely unknown. Here, we show that Fasudil could effectively inhibit EGFR-mutation cell growth and enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib by suppressing intracellular lipid accumulation. Mechanistic investigations showed that Fasudil could reverse gefitinib-induced SCD1 expression by suppressing AMPK activity, and combination therapy had a greater inactivation effect on the EGFR/PI3K/AKT pathway than either treatment alone. These findings highlight the clinical significance of Fasudil in EGFR mutation NSCLC therapy. Abstract 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.