Gefitinib has been widely used in the first‐line treatment of advanced EGFR‐mutated non‐small‐cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9‐14 months of treatment. This study revealed that Krüppel‐like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c‐Met‐overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib‐resistant NSCLC cell lines without c‐Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib‐resistant NSCLC cells with c‐Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib‐sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells by inhibiting the expression of apoptosis‐related proteins under gefitinib treatment and activating the c‐Met/Akt signaling pathway by decreasing the inhibition of β‐catenin on phosphorylation of c‐Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c‐Met overexpression.

Osimertinib is a third-generation, irreversible epidermal growth factor RTK inhibitor (EGFR-TKI) that selectively suppresses both EGFRsensitizing mutations and the T790M resistance mutation. 1 A recent clinical trial demonstrated that, compared with first-generation EGFR-TKIs in first-line clinical treatment of EGFR mutation-positive NSCLC patients, osimertinib was associated with a longer progression-free survival and promising overall survival. 1 Based on the encouraging results of the FLAURA trial, first-line treatment with osimertinib has become a favorable standard in therapies for NSCLC patients who carry the EGFR-positive mutation. Nevertheless, acquired resistance to osimertinib is also inevitable. Based on preclinical and clinical studies, various mechanisms of osimertinib resistance

The aim of the present study was to investigate the protective effect of eugenol on the transplanted heart and explore its mechanisms of action. Male Sprague-Dawley rats were randomly divided into a sham group (n=10), a eugenol group (n=10 pairs, donors and recipients) and a control group (n=10 pairs, donors and recipients). The recipients in the eugenol group received an intraperitoneal injection of eugenol (20 mg/kg/day). The sham group and the control group received equal volumes of physiological saline by intraperitoneal injection. After 15 days the recipients in the control and eugenol groups underwent abdominal heterotopic heart transplantation, while the sham group received only a coeliotomy. The orthotopic hearts in the sham group and the heterotopic hearts in the eugenol and control groups, as well as the peripheral blood samples from all three groups were taken 3 h post operation for biochemical, histopathological, molecular and apoptosis analyses. Compared with the control group, the eugenol treatment significantly reduced the myocardial malondialdehyde content, serum cardiac troponin I, creatine kinase-MB, tumor necresis factor-α and interleukin-6 levels (P<0.05) and significantly alleviated myocardial injury. Western blot analysis demonstrated that the protein expression of cleaved Poly (ADP-ribose) polymerase 1, BAX and active caspase-3 in the eugenol group were significantly decreased, while B-cell lymphoma 2 expression was significantly increased compared with the control group (P<0.05). The myocardial apoptosis rate of the eugenol group was significantly decreased compared with the control group (P<0.05). In conclusion eugenol treatment significantly reduced myocardial injury and demonstrated protective effects for the transplanted heart.