Luteolin is effective in the non‐small cell lung cancer model with L 858 R / T 790 M EGF receptor mutation and erlotinib resistance

Background and Purpose Non‐small cell lung cancer ( NSCLC ) is one of the most commonly diagnosed malignancies in the world. Small‐molecule inhibitors of the EGF receptor's tyrosine kinase domain ( TKIs) , including gefitinib and erlotinib, have been widely used for treating NSCLC . Unfortunately, nearly all patients after initially experiencing a marked improvement while on these drugs, eventually progress to acquire resistance to TKIs. Because there is no effective therapeutic strategy to treat TKI‐resistant NSCLC , we evaluated the effects of luteolin, a naturally occurring flavanoid, on T 790 M mutant NSCLC cells. Experimental Approach The effect of luteolin on the viability of NSCLC and normal cell lines was investigated using the C ell C ounting K it‐8 ( CCK ‐8) assay. Luteolin‐induced apoptosis was assessed by bivariate FITC ‐annexin V/PI assay, and W estern blots were used to measured apoptotic proteins. Co‐immunoprecipitation was used to determine the effect of luteolin on the interaction between H sp90 and mutant EGF receptors. The effect of luteolin on the A kt/m TOR pathway was studied using W estern blotting analysis. Its anti‐tumour efficacy in vivo was examined in a mouse xenograft model. Key Results Luteolin exerted significant anti‐tumourigenic effects on the EGF receptor L 858 R / T 790 M mutation and erlotinib‐resistant NSCLC both at the cellular and animal levels. Mechanistically, luteolin induced degradation of the EGF receptor by inhibiting the association of H sp90 with the mutant EGF receptor , and, therefore, prevented PI3K/Akt/mTOR signalling, which resulted in NSCLC cell apoptosis. Conclusion and Implications Luteolin may be a potential candidate for NSCLC therapy, especially for treatment of patients with acquired erlotinib‐resistant NSCLC .