SETD4 Confers Cancer Stem Cell Chemoresistance in Nonsmall Cell Lung Cancer Patients via the Epigenetic Regulation of Cellular Quiescence.

Increasing evidence indicates that quiescent cancer stem cells (CSCs) are a root cause of chemoresistance. SET domain-containing protein 4 (SETD4) epigenetically regulates cell quiescence in breast cancer stem cells (BCSCs), and SETD4-positive BCSCs are chemoradioresistant. However, the role of SETD4 in chemoresistance, tumor progression, and prognosis in nonsmall cell lung cancer (NSCLC) patients is unclear. Here, SETD4-positive cells were identified as quiescent lung cancer stem cells (qLCSCs) since they expressed high levels of ALDH1 and CD133 and low levels of Ki67. SETD4 expression was significantly higher in advanced-stage NSCLC tissues than in early-stage NSCLC tissues and significantly higher in samples from the chemoresistant group than in those from the chemosensitive group. Patients with high SETD4 expression had shorter progression-free survival (PFS) times than those with low SETD4 expression. SETD4 facilitated heterochromatin formation via H4K20me3, thereby leading to cell quiescence. RNA-seq analysis showed upregulation of genes involved in cell proliferation, glucose metabolism, and PI3K-AKT signaling in activated qLCSCs (A-qLCSCs) compared with qLCSCs. In addition, SETD4 overexpression facilitated PTEN-mediated inhibition of the PI3K-mTOR pathway. In summary, SETD4 confers chemoresistance, tumor progression, and a poor prognosis by regulating CSCs in NSCLC patients.

TROY Modulates Cancer Stem-Like Cell Properties and Gefitinib Resistance Through EMT Signaling in Non-Small Cell Lung Cancer.

Targeted therapy has made breakthrough progress in the treatment of advanced non-small cell lung cancer (NSCLC) in the last 20 years. Despite that, acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is an urgent clinical problem. Our study established an acquired gefitinib-resistant cell line, which exhibited epithelial-mesenchymal transition (EMT) and stem cell-like properties. Transcriptional sequencing and bioinformatics analysis revealed that TROY was significantly increased in gefitinib-resistant cells. Gene set enrichment analysis (GSEA) showed EMT was the core enriched hallmark in the resistant cells. TROY siRNA interference could overcome the gefitinib resistance with the downregulated expression of EMT and CSC markers. In addition, immunohistochemistry indicated that TROY was overexpressed in tumor samples from patients who acquired resistance to first-generation EGFR-TKI without T790M mutation and the expression of TROY was associated with poor prognosis in LUAD. Here, we provided the potential role of TROY in the resistance of targeted therapy and a new strategy to overcome the acquired resistance to EGFR-TKI in NSCLC.

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with bevacizumab for advanced non-squamous non-small-cell lung cancer patients with gradual progression on EGFR-TKI treatment: A cohort study.

ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve outcomes of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, acquired resistance inevitably emerges and remains a major challenge. The present study aimed to evaluate the efficacy of EGFR-TKIs plus bevacizumab in advanced non-squamous NSCLC patients with gradual progression on EGFR-TKIs.Advanced non-squamous EGFR-mutated NSCLC patients with gradual progression on EGFR-TKIs were administered bevacizumab while EGFR-TKIs were continued until disease progression occurred. Tumor lesions were assessed, and blood samples were collected at the start of the combination treatment and every 6 weeks until disease progression.Among the 15 included patients, there were no grade 3 or higher adverse events (AEs). Partial response (PR) and stable disease (SD) were achieved in 1 and 13 patients, respectively, with an objective response rate (ORR) of 6.7% and a disease control rate (DCR) of 93.3%. The median progression-free survival 2 (PFS2), defined as the time from the initiation of combination treatment to disease progression, was 5.0 (95% confidence interval [CI]: 4.0-6.0) months. Additionally, Spearman correlation analysis revealed that PFS2 was positively correlated with the serum vascular endothelial growth factor (VEGF) level at baseline (r = 0.7212, P = .0234). Patients with high baseline serum VEGF levels showed a better median PFS2 than those with low baseline serum VEGF levels (5.5 months vs 3.6 months, P = .0333).EGFR-TKIs plus bevacizumab led to a durable prolongation of PFS in non-squamous NSCLC patients with gradual progression on EGFR-TKIs. This therapeutic regimen was well tolerated and could be a promising strategy for these patients. Serum VEGF could be a potential biomarker to predict a subset of patients who are likely to benefit from EGFR-TKIs combined with bevacizumab.

Mechanism of acquired resistance to nivolumab in lung squamous cell carcinoma: case report and review of the literature.

Background: Immune checkpoint inhibitors targeting PD-1 and PD-L1 have noticeably improved the treatment landscape of advanced non-small-cell lung cancer, including lung squamous cell carcinoma (SCC). Although patients with immune checkpoint therapy can achieve long-term survival, acquired resistance has been recognized more frequently, while the underlying mechanisms are currently poorly understood. Materials and methods: Here, we report a patient with metastatic lung SCC treated with nivolumab as a first-line treatment for 28 months. Conclusion: The analysis of specimens prenivolumab and postnivolumab treatment suggests that genetic alterations in SOX2 and CDKN2A/CDKN2B and changes in the tumor microenvironment could be reasons for the acquired resistance to nivolumab observed in the lung SCC patient.

Adjuvant therapy with heparin in patients with lung cancer without indication for anticoagulants: A systematic review of the literature with meta-analysis.

BACKGROUND: The effect of heparin in improving cancer survival has gained increasing attention over the past decades. Several clinical trials have evaluated the role of heparin on survival outcome and its safety profile in lung cancer patients. Thus, we performed a systematic review and meta-analysis from the results of randomized controlled trials (RCTs) to assess the efficacy and safety of heparin in patients with lung cancer without indication for anticoagulants. METHODS: We searched PubMed, Embase, and The Cochrane Central Register of Controlled Trials databases for relevant studies. The inclusion criteria used were patients with lung cancer without a concurrent diagnosis of venous thromboembolism (VTE) and were treated with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). The outcomes included survival outcome, VTE, bleeding, major bleeding, and thrombocytopenia. The results were presented as hazard ratio (HR) and relative risk (RR), and the STATA 12.0 package was used for comprehensive quantitative analysis. RESULTS: A total of 6 studies with 753 cases and 640 controls were included for the final analysis. The meta-analysis showed significant differences in survival with an HR of 0.71 (95% confidence interval [CI] 0.60-0.84), particularly in limited-stage small cell lung cancer (SCLC) with an HR of 0.57 (95% CI 0.43-0.77), and also in VTE (RR 0.46; 95% CI 0.27-0.80) when heparin was compared with placebo or no anticoagulant. There were no significant differences in risks for bleeding (RR 1.53; 95% CI 0.96-2.45), major bleeding (RR 1.43; 95% CI 0.59-3.45), and thrombocytopenia (RR 0.86; 95% CI 0.66-1.12). CONCLUSION: Administration of heparin (mainly LMWH) as primary thromboprophylaxis for lung cancer patients without indication for anticoagulants was associated with a significant survival benefit, particularly in limited-stage SCLC.

Determination of cholesterol and four phytosterols in foods without derivatization by gas chromatography-tandem mass spectrometry.

In this study, a method for determination of cholesterol and four phytosterols by gas chromatography coupled with electron impact ionization mode-tandem mass spectrometry without derivatization in general food was developed. The sample was saponified with 7.5% KOH in methanol. After heating on hot plate and reflux for 60 minutes, the saponified portion was extracted with n-hexane/petroleum ether (50:50, v/v). The extracts were evaporated with rotary evaporator and then redissolved with tetrahydrofuran. The tetrahydrofuran layer was transferred into an injection vial and analyzed by gas chromatography on a 30 m VF-5 column. Limit of quantification was 2 mg/kg. Recoveries of cholesterol and four phytosterols from general food were between 91% and 100%.