Despite initial dramatic efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR‐TKIs) in EGFR‐mutant lung cancer patients, subsequent emergence of acquired resistance is almost inevitable. Resveratrol and its derivatives have been found to exert some effects on EGFR‐TKI resistance in non‐small cell lung cancer (NSCLC), but the underlying mechanisms remain unclear. We screened several NSCLC cell lines with gefitinib resistance by MTT assay and analysed the miR‐345/miR‐498 expression levels. NSCLC cells were pre‐treated with a resveratrol derivative, trans‐3,5,4‐trimethoxystilbene (TMS) and subsequently challenged with gefitinib treatment. The changes in apoptosis and miR‐345/miR‐498 expression were analysed by flow cytometry and q‐PCR respectively. The functions of miR‐345/miR‐498 were verified by CCK‐8 assay, cell cycle analysis, dual‐luciferase reporter gene assay and immunoblotting analysis. Our results showed that the expression of miR‐345 and miR‐498 significantly decreased in gefitinib resistant NSCLC cells. TMS pre‐treatment significantly upregulated the expression of miR‐345 and miR‐498 increasing the sensitivity of NSCLC cells to gefitinib and inducing apoptosis. MiR‐345 and miR‐498 were verified to inhibit proliferation by cell cycle arrest and regulate the MAPK/c‐Fos and AKT/Bcl‐2 signalling pathways by directly targeting MAPK1 and PIK3R1 respectively. The combination of TMS and gefitinib promoted apoptosis also by miR‐345 and miR‐498 targeting the MAPK/c‐Fos and AKT/Bcl‐2 signalling pathways. Our study demonstrated that TMS reduced gefitinib resistance in NSCLCs via suppression of the MAPK/Akt/Bcl‐2 pathway by upregulation of miR‐345/498. These findings would lay the theoretical basis for the future study of TMS for the treatment of EGFR‐TKI resistance in NSCLCs.

Lung cancer is the leading cause of cancer-related death worldwide. Here we demonstrate that elevated expression of dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant t-DARPP promote lung tumor growth, while abrogation of DARPP-32 expression in human non-small-cell lung cancer (NSCLC) cells reduces tumor growth in orthotopic mouse models. We observe a physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NF-κB2) signaling. Bioinformatics analysis of 513 lung adenocarcinoma patients reveals that elevated t-DARPP isoform expression is associated with poor overall survival. Histopathological investigation of 62 human lung adenocarcinoma tissues also shows that t-DARPP expression is elevated with increasing tumor (T) stage. Our data suggest that DARPP-32 isoforms serve as a negative prognostic marker associated with increasing stages of NSCLC and may represent a novel therapeutic target.

Background: Recent studies suggest that tumor fusion burden (TFB) is a hallmark of immune infiltration in prostate cancer, the correlation of TFB with immune microenvironment, and genomic patterns in head and neck squamous cell carcinomas (HNSC) remain largely unclear.Methods: Gene fusion, genomic, transcriptomic, and clinical data of HNSC patients from the cancer genome atlas (TCGA) database were collected to analyze the correlation of TFB with mutation patterns, tumor immune microenvironment, and survival time in HNSC patients.Results: Human papillomavirus (HPV) (−) patients with low TFB exhibited significantly enhanced CD8+ T cells infiltration and cytolysis activity and increased level of interferon‐gamma (IL‐γ), human leukocyte antigen (HLA) class I, and chemokines. Moreover, TFB was positively correlated with TP53 mutation, score of gene copy number, and loss of heterozygosity (LOH), as well as the biological progress of epithelial‐mesenchymal transition (EMT), metastasis, and stem cell characteristics. Further analysis revealed that HPV (−) HNSC patients with low TFB have a better prognosis.Conclusions: Our data revealed the correlation of TFB with tumor immune microenvironment and predictive features for immunotherapy, implying tumors with low TFB may be potential candidates for immunotherapeutic agents. Moreover, the TFB low group had prolonged overall survival (OS) in the HPV (−) HNSC cohort.