Genistein (GEN) has been previously reported to enhance the radiosensitivity of cancer cells; however, the detailed mechanisms remain unclear. Here, we report that GEN treatment inhibits the cytoplasmic distribution of Bcl-xL and increases nuclear Bcl-xL in non-small cell lung cancer (NSCLC). Interestingly, our in vitro data show that ionizing radiation IR treatment significantly increases IR-induced DNA damage and apoptosis in a low cytoplasmic Bcl-xL NSCLC cell line compared to that of high cytoplasmic Bcl-xL cell lines. In addition, clinical data also show that the level of cytoplasmic Bcl-xL was negatively associated with radiosensitivity in NSCLC. Furthermore, we demonstrated that GEN treatment enhanced the radiosensitivity of NSCLC cells partially due to increases in Beclin-1-mediated autophagy by promoting the dissociation of Bcl-xL and Beclin-1. Taken together, these findings suggest that GEN can significantly enhance radiosensitivity by increasing apoptosis and autophagy due to inhibition of cytoplasmic Bcl-xL distribution and the interaction of Bcl-xL and Beclin-1 in NSCLC cells, respectively.

Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer (NSCLC) patients confers a worse quality of life and prognosis. The efficacy comparison of two first-generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib as first-line treatment for CNS metastasis NSCLC patients with EGFR-sensitizing mutations is yet to be elucidated. A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefitinib as first-line treatment for advanced NSCLC patients with EGFR-sensitizing mutations. Time to neurological progression (nTTP) and median progression-free survival (mPFS) were calculated. The study involved 279 patients (erlotinib group: 108, gefitinib group: 171). After a median follow-up of 22 months, 27 patients (25%) in the erlotinib group and 60 patients (35.1%) in the gefitinib group showed CNS progression. The HR of CNS progression for erlotinib versus gefitinib was 0.695 [95% confidence interval (CI), 0.406–1.190], suggesting a risk reduction of 30.5% although not achieving statistical significance. The 6-, 12- and 18-month cumulative CNS progression rates were 0.9, 3.7 and 12% for erlotinib compared with corresponding rates of 5.8, 9.4 and 17% for gefitinib (P = 0.181). However, for those patients with preexisting brain metastases prior to EGFR-TKI treatment, erlotinib as first line treatment significantly extended the median nTTP in comparison to gefitinib (30 months vs 15.8 months, p = 0.024). Our data show that nTTP can be effectively extended in preexisting brain metastases patients with EGFR-sensitizing mutations initially treated with erlotinib compared with gefitinib. If confirmed, our results indicate that erlotinib may play an important role in controlling CNS progression from EGFR mutation-positive NSCLC.

Objective:To examine the association of tag single nucleotide polymorphisms (tagSNPs) (rs1130409, rs1760944, rs2307486 and rs3136817) in APEX1 with the risk of severe radiation-induced pneumonitis (RP) after radiotherapy among Han Chinese patients with lung cancer.Methods:A total of 168 patients with lung cancer who were receiving radiotherapy were prospectively recruited. RP was evaluated according to the Radiation Therapy Oncology Group. A case–control study was performed. The case group included patients with RP grade of ≥3, while the control group comprised patients with RP grades <3. Four tagSNPs of APEX1 were genotyped in 126 patients with complete follow-up by multi-SNaPshot® (Genesky Biotechnologies Inc., Shanghai, China) genotyping assays. Results were assessed by a logistic regression model for RP risk and Mantal–Cox log-rank test for the cumulative RP probability by the genotypes.Results:rs1130409 was associated with severe RP. GT genotype of rs1130409 was significantly higher in patients with ...

Background: Early data has indicated that EGFR 19Del mutation and EGFR L585R mutation are two different types of non‐small cell lung cancer (NSCLC). However, how the different molecular mechanisms participate in the process of mediastinal lymph node metastasis (MLNM) in lung adenocarcinoma (LA) harboring EGFR 19Del and EGFR L858R mutation remains unknown. We thus explored the genes responsible for MLNM in LA with EGFR 19Del or L858R mutation.Methods: We performed transcriptome sequencing and bioinformatics analysis from 10 patients with LA resection specimens of primary tumors. Quantitative reverse transcription‐polymerase chain reaction was used to validate gene expressions.Results: There were 69 mRNAs upregulated and 100 mRNAs downregulated in five samples with MLNM compared with samples without MLN metastasis. EEF1A2 and ERN2 were observed exhibiting different expression patterns in EGFR 19Del and EGFR L858R samples with MLNM. In samples harboring EGFR 19Del mutation, the expression of EEF1A2 gene in samples with MLNM was significantly lower compared with samples without MLN metastasis, and in samples with EGFR L858R, it was significantly higher in samples with MLNM. The expression pattern of ERN2 was opposite to EEF1A2. In addition, several other genes including SLC6A11, IGHV3‐48, IGHV3‐43, DUSP9, and HOXA9 were also shown to be associated with invasion and metastasis and exhibited an expression pattern similar to EEF1A2 and ERN2 in EGRF 19Del and L858R mutation tumors.Conclusions: EEF1A2 and ERN2 were for the first time observed exhibiting distinct expression patterns in MLNM in lung adenocarcinomas harboring EGFR 19Del and EGFR L858R mutation by interindividual DEGs analysis.Key points: Significant findings of the studyIn our study, we focused on the mechanisms of metastasis and invasion that different EGFR mutations conferred and identified two critical genes separately involved in this process in EGFR 19Del and L858R mutation tumors.What this study addsOur findings not only reinforced theoretical foundations that the EGFR 19Del and L858R mutation tumors should be considered as two kinds of diseases, but also laid the fundamentals for precise determination of the mediastinal lymph node radiation field and improvement of clinical outcome.

Background: This study was undertaken to investigate the expression of programmed death-ligand 1 (PD-L1) in the pulmonary primary tumor and brain metastases (BM) tumor as well as neutrophil-to-lymphocyte ratio (NLR) in preoperative peripheral blood samples in advanced non-small cell lung cancer. The potential association between both PD-L1 expression and NLR value and therapeutic sensitivity along with prognosis was explored. Methods: Eleven patients pathologically confirmed as non-small cell lung cancer (NSCLC) with BM were enrolled. The expression of PD-L1 in pulmonary primary tumor and BM tumor was evaluated with immunohistochemistry. NLR value was calculated from blood cell count. DFS and OS were calculated using the Kaplan-Meier method, and the log-rank test was used to assess differences between groups. Results: High expression of PD-L1 was observed in 4 pulmonary primary tumors and 3 BM tumors respectively. The NLR in peripheral blood before brain surgery was shown to be efficient to discriminate patients whose brain metastatic lesion reached disease control from others (AUC: 0.917 95% CI: 0.731–1.000, P=0.041). Five patients had an NLR value higher than the cutoff value of 3.0553. Eight patients with low expression of PD-L1 in BM lesions had 27 months of median OS, which was signifcantly longer than patients with high expression of PD-L1 with 10 months of median OS (Log-Rank, P=0.012). Five patients with both low expression of PD-L1 in BM lesions and low NLR value (≤3.0553) reached 36 months mOS significantly longer than others with only 10 months of mOS (Log-Rank, P=0.034, HR =0.133, 95% CI: 0.861–65.819, P=0.068). Conclusions: High expression of PD-L1 along with high NLR value is associated with less sensitivity of response to treatment and poor prognosis.