Differences of genomic alterations and heavy metals in non-small cell lung cancer with different histological subtypes.

PURPOSE: This study aimed to explore the correlations among heavy metals concentration, histologic subtypes and molecular characteristics in patients with non-small cell lung cancer (NSCLC). METHODS: In this study, an NGS panel of 82 tumor-associated genes was used to identify genomic alternations in 180 newly diagnosed patients with NSCLC. The concentrations of 18 heavy metals in the serum samples were detected by inductively coupled plasma emission spectrometry (ICP-MS). RESULTS: A total of 243 somatic mutations of 25 mutant genes were identified in 115 of 148 patients with LUAD and 45 somatic mutations of 15 mutant genes were found in 24 of 32 patients with LUSC. The genomic alternations, somatic interactions, traditional serum biomarkers, and heavy metals were markedly different between patients with LUAD and LUSC. Moreover, patients with LUSC were significantly positively correlated with Ba, but not LUAD. Lastly, patients with EGFR mutations presented significant negative correlations with Cd and Sr, whereas patients with TP53 mutations showed a significant positive correlation with Pb. CONCLUSION: The genomic alternations, somatic interactions, traditional serum biomarkers, and heavy metals were different between patients with LUAC and LUSC, and heavy metals (e.g., Ba, Pb, and Cd) may contribute to the tumorigenesis of NSCLC with different histological and molecular subtypes.

EGFR tyrosine kinase inhibitors alone or in combination with chemotherapy for non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials.

OBJECTIVE: The objective of this study was to perform a meta-analysis comparing the efficiency of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy to EGFR TKI treatment alone in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Following keyword queries in databases and identification of randomized control trials for inclusion, hazard ratios (HRs), relative risks (RRs), and associated 95% confidence intervals (95% CIs) were determined. RESULTS: Ten randomized controlled trials involving 1354 participants with NSCLC were evaluated. We found that a combined approach of chemotherapy with EGFR TKIs significantly improved overall survival (OS) compared with EGFR TKI alone in our patient cohort (HR = 0.47, 95% CI = 0.31-0.72). In addition, a higher overall response rate (ORR) was found for patients who received combined treatment compared to chemotherapy alone (RR = 2.17, 95% CI = 1.51-3.12). Furthermore, concomitant use of chemotherapy with TKIs significantly improved the progression-free survival (PFS) when compared to the use of TKIs alone (HR = 0.68, 95% CI = 0.49-0.95). Moreover, there was a higher ORR among patients who received combined treatment as compared to those who were managed using TKIs only (RR=1.17, 95%CI=1.09-1.25). CONCLUSION: Our meta-analysis shows that EGFR TKIs with chemotherapy confer better OS and ORR compared to either treatment alone, similarly, the combined treatment showed better PFS and ORR profiles than the use of TKI alone.

Radiosensitization of HER2-positive esophageal cancer cells by pyrotinib.

Radiation therapy is a widely used treatment for esophageal cancer. However, radiation resistance might result in a poor prognosis. Overexpression of HER2 has been related to adaptive radiation resistance. Pyrotinib is a HER2 inhibitor that shows an anti-tumor effect in breast cancer. The present study aims to explore the influence of pyrotinib combined with radiotherapy on HER2-positive esophageal cancer cells and explore the underlying mechanism. We screened two cell lines (TE-1 and KYSE30) that highly express HER2 from several human esophageal cancer cell lines. Cells were treated with pyrotinib or/and radiation. Cell proliferation, cell cycle distribution, and cell migration were measured. The protein levels involved in cell cycle and DNA repair were measured by Western blot. Results showed that pyrotinib inhibited HER2 activation and exerted an anti-proliferative effect in TE-1 and KYSE30 cells. Furthermore, it enhanced the anti-proliferative effect of radiation in these two cell lines. These effects might be via inhibiting HER2 phosphorylation, inducing G0/G1 arrest, and reducing EMT and DNA repair. Our results indicated that pyrotinib sensitivitied HER2 positive esophageal cancer cells to radiation treatment through various mechanisms. These findings may provide a new therapeutic strategy for treating HER2 positive esophageal cancer.

UGT2B17 and miR-224 contribute to hormone dependency trends in adenocarcinoma and squamous cell carcinoma of esophagus.

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA) are the two main subtypes of esophageal cancer. Genetics underpinnings of EA are substantially less understood than that of ESCC. A large-scale relation data analysis was conducted to explore the genes implicated with either EA or ESCC, or both. Each gene linked to ESCC but not EA was further explored in mega-analysis of six independently collected EA RNA expression datasets. A multiple linear regression (MLR) model was built to study the possible influence of sample size, population region, and study date on the gene expression data in EA. Finally, a functional pathway analysis was conducted to identify the possible linkage between EA and the genes identified as novel significant contributors. We have identified 276 genes associated with EA, 1088 with ESCC, with a significant (P<5.14e-143) overlap between these two gene groups (n=157). Mega-analysis showed that two ESCC-related genes, UGT2B17 and MIR224, were significantly associated with EA (P-value <1e-10), with multiple connecting pathways revealed by functional analysis. ESCC and EA share some common pathophysiological pathways. Further study of UGT2B17 and MIR224, which are differentially dysregulated in ESCC and EA tumors, is warranted. Enhanced expression of UGT2B17 and the lack of miR-224 signaling may contribute to the responsiveness of EA to the male sex steroids.

Pyrotinib treatment on HER2-positive gastric cancer cells promotes the released exosomes to enhance endothelial cell progression, which can be counteracted by apatinib.

Aims: Pyrotinib is a newly developed irreversible pan-ErbB receptor tyrosine kinase inhibitor for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers, and clinic trials of pyrotinib in treatment of HER2-positive gastric cancer (GC) are underway. Exosomes are tiny vesicles secreted by cancer cells and take essential roles in the progression of carcinoma. Whether pyrotinib application has any effect on the cancer cell-released exosomes has not been studied. The aim of our work was to address if pyrotinib treatment impacts the effect of HER2-positive GC cell-derived exosomes on endothelial cell (EC) progression. Methods: Isolation of exosomes released by HER2-positive NCI-N87 and MKN45 lines after pyrotinib treatment was performed. Then, human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of exosomes to address their proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Effect of pyrotinib-treated exosomes at concentration of 10 µg/mL was compared to that without pyrotinib treatment over 96-hr time course. Transwell assay and wound-healing assay were carried out by incubating with exosomes released by NCI-N87 and MKN45 cells with/without pyrotinib treatment over 24-hr time course. The aforementioned experiments were done under same conditions in order to evaluate the combined effect of apatinib and pyrotinib on HUVEC motility and invasive capacity. Results: We showed that HUVEC proliferation, motility and invasive capacity were further enhanced upon incubation with exosomes released by pyrotinib-treated GC cell lines, compared to those without pyrotinib treatment. Significantly, this effect was counteracted by the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor apatinib which inhibits EC progression. Conclusion: Our study suggests that pyrotinib application on HER2-positive GC produces stronger exosomes that promote the proliferation and motility of vascular ECs, and combination of pyrotinib with apatinib provides potentially better therapy.

Prognostic value of ribonucleotide reductase subunit M1 (RRM1) in non-small cell lung cancer: A meta-analysis.

BACKGROUND: Ribonucleotide reductase subunit 1 (RRM1) is a potential prognostic factor for non-small cell lung cancer (NSCLC). This study evaluates prognostic value of RRM1 in NSCLC patients by meta-analyzing outcomes reported in literature. METHOD: Data were acquired from research articles retrieved after literature search in online databases. Random effects meta-analyses were conducted by pooling hazard ratios (HR). Meta-analyses of standardized mean differences (SMD) were used to evaluate overall survival (OS) and progression-free survival (PFS) between low and high RRM1 expression groups. Metaregression analyses were conducted to evaluate the factors that could affect prognostic relationship of RRM1 with treatment and survival outcomes. RESULTS: 23 studies (3148 patients) were included. RRM1 expression was not meaningfully associated with prognosis of NSCLC even when the reference (HR = 1) was either low RRM1 expression (0.918 [95% CI 0.833, 1.003]) or high RRM1 expression (0.834 [0.625, 1.043]). OS was significantly longer in low RRM1 expression group compared to high RRM1 expression group (SMD 0.73 [0.36, 1.09]; P < 0.0001). PFS was not significantly different between low and high RRM1 expression groups (SMD 0.08 [-0.29, 0.45]; p = 0.68). Age was inversely associated with HR (p = 0.001) even when reference was low RRMI (p = 0.027) or high RRM1 (p = 0.006). Age was positively associated with OS in both low and high RRM1 groups. CONCLUSION: In meta-analysis of studies which used gemcitabine-based therapies, higher RRM1 expression is found to associated with shorter OS but not PFS. HR depicting relationship between RRM1 expression and OS/PFS/treatment response could not demonstrate a prognostic role of RRM1 in NSCLC patients.