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Epidermal growth factor receptor (EGFR) mutations are often associated with non-EGFR genetic alterations, which may be a reason for the poor efficacy of EGFR tyrosine kinase inhibitors (TKIs). Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant non-EGFR genetic alterations were retrospectively collected. And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy. Demographic, clinical and pathological data were collected, and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression. Survival data were obtained through face-to-face or telephone follow-up. The differences between the two groups in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were investigated.107 patients were included, including 63 cases in the combination group and 44 cases in the monotherapy group. The ORR were 78% and 50% (P=0.003), and DCR were 97% and 77% (P=0.002), respectively. At a median follow-up of 13.7 mon, a PFS event occurred in 38.1% and 81.8% of patients in the two groups, with median PFS of 18.8 mon and 5.3 mon, respectively (P0.000,1). Median OS was unreached in the combination group, and 27.8 mon in the monotherapy group (P=0.31). According to the Cox multivariate regression analysis, combination therapy was an independent prognostic factor of PFS CONCLUSIONS: In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations, combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy, which should be the preferred treatment option.

Studies have found that lncRNA SENCR (lncSENCR) is closely related to the progress of human cancer. This study aimed to investigate the biological and clinical roles of lncSENCR in non-small cell l...

Long non-coding RNAs (lncRNAs) are key mediators of cancer. The dysregulation of a lncRNA, CASC15, has been linked to several cancers, except lung cancer. Here, the aim of the study was to explore the role and mechanism of CASC15 in lung cancer regulation, with the focus on its interaction with a potential target, microRNA-766-5p (miR-766-5p) and an oncogene, kallikrein-related peptidase 12 (KLK12). Quantitative real-time PCR (qRT-PCR) was used to assess levels of CASC15, miR-766-5p and KLK12 in lung cancer tissues or cells. Western blot analysis was used to detect KLK12 protein expression. Ectopic expression of CASC15 was induced by a lentiviral system. CCK-8 and transwell assays were used to evaluate lung cancer cell proliferation and invasion, respectively. The interaction among CASC15, miR-766-5p and KLK12 was investigated by bioinformatical analysis and luciferase assay. In lung cancer tissue and cells, CASC15 was upregulated, while miR-766-5p was downregulated. Overexpression of CASC15 promoted lung cancer cell proliferation and invasion. A negative correlation was found between CASC15 and miR-766-5p levels. Overexpression of miR-766-6p reversed the cancer-promoting role of CASC15 in lung cancer cells, which was mediated by KLK12. The tumor-promoting role of CASC15 and tumor-suppressing role of miR-766-5p were also validated in vivo in tumor bearing mice, and KLK12 was also shown as an important mediator. CASC15 promotes lung cancer through the miR-766-5p/KLK12 axis, indicating that CASC15 is a potential therapeutic in lung cancer.

Background Personalized cancer vaccines based on tumor-derived neoantigens have shown strong and long-lasting antitumor effect in patients with some solid tumors. However, whether neoantigens identified from primary lesions could represent their metastatic lesions, and consequently the effect of vaccine therapy remained unknown. Methods To investigate whether neoantigens identified from primary tumors are similar to their matched metastases in lung cancer, we identified 79 samples from 24 cases. All of samples were collected before any systemic therapy. Major criteria for neoantigen identification included: derived from tumor-specific mutations, fold change >10 comparing to germline expression level, high predicted human leukocyte antigen (HLA) binding affinity and peptide of 9-11 amino acids in length. Results We found a wide range of tumor neoantigen burden in both primaries and metastases. The counts, overall distribution pattern and predicted HLA binding affinity of neoantigens were similar between primaries and metastases. However, only 20% of shared neoantigens (presented in both primaries and metastases) was observed, which were mainly derived from single nucleotide variants (SNVs) and fusions. A variety of corresponding HLA alleles were observed and 50.0% of cases were HLA-C*06:02. Finally, we observed the neoantigen intrametastases homogeneity in patients with sole brain metastases. Conclusions Neoantigen landscape in terms of the number, type and predicted HLA binding affinity was similar between primaries and metastases, but the percentage of shared neoantigens is only modest, suggesting vaccine development based solely on primary tumor neoantigen may not offer optimal therapeutic outcome, and shared neoantigen needs to be seriously considered.

Background Lung cancer is the major cause of cancer-related death worldwide, and 80% patients of lung cancer are non-small-cell lung cancer (NSCLC) cases. MicroRNAs are important gene regulators with critical roles in diverse biological processes, including tumorigenesis. Studies indicate that sphingosine kinase 2 (SphK2) promotes tumor progression in NSCLC, but how this occurs is unclear. Thus, we explored the effect of miR-338-3p targeting SphK2 on proliferation and apoptosis of NSCLC cells. Methods Expression of miR-338-3p and SphK2 in NSCLC A549 and H1299 cell lines was measured using qRT-PCR and Western blot. CCK-8 and colony formation assays were used to assess the effect of miR-338-3p on NSCLC cell line proliferation. Flow cytometry was used to study the effect of miR-338-3p on NSCLC apoptosis. Luciferase reporter assay and Western blot were used to confirm targeting of SphK2 by miR-338-3p. Finally, in vivo tumorigenesis studies were used to demonstrate subcutaneous tumor growth. Results miR-338-3p expression in 34 NSCLC clinical samples was downregulated and this was correlated with TNM stage. miR-338-3p significantly suppressed proliferation and induced apoptosis of NSCLC A549 and H1299 cells in vitro. SphK2 was a direct target of miR-338-3p. Overexpression of miR-338-3p significantly inhibited SphK2 expression and reduced luciferase reporter activity containing the SphK2 3′-untranslated region (3′-UTR) through the first binding site. SphK2 lacking 3′-UTR restored the effects of miR-338-3p on cell proliferation inhibition. miR-338-3p significantly inhibited tumorigenicity of NSCLC A549 and H1299 cells in a nude mouse xenograft model. Conclusions Collectively, miR-338-3p inhibited cell proliferation and induced apoptosis of NSCLC cells by targeting and down-regulating SphK2, and miR-338-3p could inhibit NSCLC cells A549 and H1299 growth in vivo, suggesting a potential mechanism of NSCLC progression. Therapeutically, miR-338-3p may serve as a potential target in the treatment of human lung cancer.

The number of new lung cancer cases diagnosed yearly is high, and the mortality rate has not substantially declined. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and adenocarcinoma accounts for the largest proportion of NSCLC. Currently, platinum-based combined chemotherapy, particularly cisplatin (DDP) is still the main form of treatment for advanced NSCLC. However, cisplatin resistance often occurs in patients who receive chemotherapy. Previous studies offer various explanations for how miRNAs affect cisplatin resistance, but the underlying mechanism remains largely unknown. The present study was designed to focus on miR-203 and Dickkopf-1 (DKK1), investigating the potential mechanisms involved in cisplatin resistance in tissues of lung adenocarcinoma and A549/H460 cell lines. In DDP-sensitive NSCLC samples, miR-203 was expressed at a higher level when compared with this level in DDP-insensitive samples, while DKK1 mRNA was expressed at a relatively low level as indicated by qRT-PCR. Dual luciferase reporter assay revealed that DKK1 is a target gene of miR-203 in A549 and H460 cells. Upregulation of miR-203 reduced the IC50 value of cisplatin in the A549 and H460 cells by inhibiting cell growth and promoting cell apoptosis. Similar effects of tumor inhibition and cisplatin sensitization were verified in vivo. Further research showed that both overexpression of miR-203 and knockdown of DKK1 increased the sensitization to DDP with a lower IC50 value. Upon DKK1 knockdown, overexpression of miR-203 had no added effects on the sensitivity of the cells. In addition, miR-203 was unable to sensitize cells with DKK1 that lacked the 3' untranslated region (3'UTR). We conclude that miR-203 targets the 3'UTR of DKK1, and increases cisplatin sensitivity in A549/H460 cell lines.

This study aimed to determine whether there is a difference in the efficacy of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) presenting with or without brain metastases. Patients with advanced NSCLC treated with nivolumab monotherapy were retrospectively analyzed. They were divided into two cohorts according to the presence or absence of brain metastases. The differences between the two cohorts in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS) were investigated, and the intracranial efficacy, including intracerebral objective response rate (IORR), intracranial disease control rate (IDCR) and intracranial progression-free survival (iPFS), were examined in the brain metastasis (BM) cohort. Seventy-three patients (32 with brain metastases and 41 without) were included. The ORRs of the BM cohort and the non-brain metastasis (non-BM) cohort were 25.0% and 19.5% (p = 0.574), DCRs were 53.1% and 56.1% (p = 0.800), respectively. Their median PFS were 2.8 and 4.9 months (p = 0.204), median DORs were 9.8 and 28.8 months (p = 0.003), and median OS were 14.8 and 20.2 months (p = 0.114), respectively. According to the Cox multivariate regression analysis, BM was not an independent prognostic factor. The IORR and IDCR of the BM cohort were 28.1% and 46.9%, respectively, with a median iPFS of 2.2 months. The efficacy of nivolumab is comparable in patients with NSCLC presenting with and without brain metastases, but the results must be verified in large-scale prospective studies.

Background: To investigate whether neoantigens identified from primary tumors are similar to their matched metastases in lung cancer. Methods: Primary lesions, matched metastases and peripheral blood were collected before systemic therapy. We used following major criteria for neoantigen identification: derived from tumor-specific mutations, fold change > 10 comparing to germline expression level, high predicted human leukocyte antigen (HLA) binding affinity (IC 50 < 500 nM) and peptide of 9-11 amino acids in length. Findings: 79 samples from 24 cases were identified, including 10 with liver metastasis (LM), 10 with brain metastasis (BM) and 4 with sole BM. A wide range of tumor neoantigen burden was identified in both primaries (median 214, range 54-2992) and metastases (median 178, range 34-2488). The counts, overall distribution pattern and predicted HLA binding affinity of neoantigens were similar between primaries and metastases. However, only a low percentage of shared neoantigens (presented in both primaries and metastases) was observed, which were mainly derived from single nucleotide variants and fusions. A variety of corresponding HLA alleles were observed and HLA-C*06:02 was found in 10 cases (50.0%). Additionally, neoantigen intratumor homogeneity with a low percentage of shared neoantigens was observed in sole BM. Interpretation: Although neoantigen landscape in terms of the number, type and predicted HLA binding affinity was found similar between primaries and metastases, the percentage of shared neoantigens is only modest, suggesting vaccine development based solely on primary tumor neoantigen may not offer optimal therapeutic outcome, and shared neoantigen needs to be seriously considered. Funding Statement: This study was supported in part by grants from the National Natural Science Foundation of China (No. 81772467, 81871865, 81874036 and 81972167), the Backbone Program of Shanghai Pulmonary Hospital (NO. FKGG1802), “Shuguang Program” supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission (No. 16SG18). Declaration of Interests: Henghui Zhang and Ji He is employee of Beijing Genecast Biotechnology Co., Beijing, China. Ying He and Renhong Tang are employee of Shanghai Hengrui Pharmaceutical Co. LTD, Shanghai, China. The other authors declare no potential conflict of interest. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board of each center. Informed consent was obtained before sample collection. This study was conducted in accordance with the Declaration of Helsinki.

Currently, lung cancer is still a main cause of malignancy-associated death worldwide. Even though various methods for prevention and treatment of lung cancer have been improved in recent decades, the 5-year survival rate has remained very low. Insights into the anticancer function of small-molecule anticancer compounds have opened our visual field about cancer therapy. α-Solanine has been well studied for its antitumor properties, but its effect in lung cancer and associated molecular mechanisms have not yet been evaluated. To explore the anticancer function of α-solanine, we performed an MTT assay, Transwell arrays, colony-forming survival assay, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and dual luciferase reporter assays in A549 and H1299 cells. We found that α-solanine not only inhibited cell migration and invasion ability but also enhanced the chemosensitivity and radiosensitivity of A549 and H1299 cells. Moreover, we discovered that α-solanine could affect the expression of miR-138 and focal adhesion kinase (FAK), both of which were also found to affect the chemosensitivity and radiosensitivity of A549 and H1299 cells. In conclusion, α-solanine could affect miR-138 and FAK expression to restrict cell migration and invasion and enhance the chemosensitivity and radiosensitivity of A549 and H1299 cells. The α-solanine/miR-138/FAK cascade can probably be a potential therapy target against lung adenocarcinoma.

Whether bisphosphonates could enhance the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation and bone metastases (BM) remains unknown. EGFR mutation status were collected from 1560 patients with NSCLC and BM. 356 NSCLC patients with EGFR mutation and BM were identified. Among them, 91 patients received EGFR-TKIs alone and 105 patients received EGFR-TKIs plus bisphosphonates as first-line therapy. Comparing to TKIs alone, EGFR-TKIs plus bisphosphonates had a statistically significant longer progression-free survival (PFS: 11.6 vs. 9.3 months; HR = 0.68, P = 0.009), while a similar overall survival (OS: 20.5 vs. 19.5 months; HR = 0.95, P = 0.743) in patients with EGFR-mutant NSCLC and BM. The incidence of skeletal-related events in combined group was numerically lower than that in EGFR-TKIs alone group (29.7% vs. 39.4%, P = 0.147). In multivariate analysis, EGFR mutation was found to be a significant independent prognostic factor for OS in NSCLC patients with BM (HR = 0.710, P = 0.021). In conclusion, EGFR mutation was the significant independent prognostic factor for OS and the addition of bisphosphonates to EGFR-TKIs could enhance the antitumor effect of EGFR-TKIs in patients with EGFR-mutant NSCLC and BM.

Drug resistance is the major obstacle for the successful therapy of lung adenocarcinoma. It was suggested that ß-elemene, a major isoform of elemene, could reverse the drug resistance in lung cancer cells. However, the underlying mechanisms remains poorly known. Here, we aimed to investigate whether elemene is involved in the cisplatin (DDP)-resistance of lung adenocarcinoma cells and further explore the underlying mechanism. The results showed that human lung adenocarcinoma cell line SPC-A-1 and its DDP-resistant strain SPC-A-1/DDP had a similar sensitivity to elemene treatment. Low dose elemene increased the sensitivity of SPC-A-1/DDP cells to DDP, accompanied by a dramatically decrease in expression of multidrug-resistance proteins and cell proliferation, and an increase in cell autophagy and autophagic apoptosis. We found that the expression of Beclin-1, the key regulator of autophagy, was induced by elemene treatment in a dose-dependent manner. Furthermore, we found that Beclin-1 overexpression had a similar effect with elemene treatment on autophagy and autophagic apoptosis in SPC-A-1/DDP cells. In contrast, Beclin-1 knockdown could significantly rescue elemene-induced autophagic apoptosis and counteract elemene-induced sensitivity in SPC-A-1/DDP cells. Our findings demonstrate that elemene can reverses the drug resistance of SPC-A-1/DDP cells via promotion of Beclin-1-induced autophagy.

Background Non-small cell lung cancer (NSCLC) is the largest histological subgroup of lung cancer and has increased in prevalence in China over the past 5 years. The 5-year survival rate has remained at 15–20 %, with a median survival of 8–12 months. The tumorigenesis and progression of NSCLC is orchestrated by numerous oncogene and anti-oncogene mutations and insights into microRNA function have increased our understanding of the process. Here, we investigated the effects of miR-30b on NSCLC cell invasion and migration and explored the underlying molecular mechanisms involved. Methods Quantitative reverse transcription PCR, wound healing assay, trans-well assays, western blotting and dual luciferase assays were performed to investigate the molecular mechanisms of miR-30b in NSCLC cells. Results MiR-30b was down-regulated and Cthrc1 up-regulated in NSCLC tissues. Both were associated with tumor differentiation, TNM stage and lymph node metastases. Up-regulation of miR-30b restricted A549 and Calu-3 cell invasion and migration. Additionally, the expression of Cthrc1, matrix metalloproteinase-9 and matrix metalloproteinase-2 was reduced, while metallopeptidase inhibitor-1 expression increased. Bioinformatics analysis identified Cthrc1 as a target of miR-30b and western blotting and luciferase reporter assays confirmed that miR-30b regulates Cthrc1 by directly binding to its 3′UTR. Transfection of Cthrc1 without the 3′UTR restored the miR-30b inhibiting cell invasion. Up-regulation of miR-30b or down-regulation of Cthrc1 had potential significance in the invasion and metastasis of NSCLC. Conclusions MiR-30b was down-regulated and Cthrc1 up-regulated in NSCLC tissues. Both of them were related to tumor differentiation, TNM stage and lymph node metastases. MiR-30b affected NSCLC cells invasion and migration by regulating Cthrc1.

Background The risk factors for liver metastasis (LM) in patients with non–small-cell lung cancer (NSCLC) remain unknown. Whether LM predicts for the effect of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant NSCLC needs to be explored. Patients and Methods A total of 598 NSCLC patients from 3 centers underwent EGFR testing, and 293 had EGFR-mutant NSCLC. Of the 598 NSCLC patients, 99 had LM; 56 patients with EGFR-mutant NSCLC received EGFR-TKIs as first-line therapy. Results EGFR mutation was not associated with LM in NSCLC patients (relative ratio, 1.305, P = .261). In the EGFR-mutant group that received first-line EGFR-TKIs, patients with LM had shorter progression-free survival (PFS; 7.5 vs. 11.8 months; P = .0003) and overall survival (OS; 20.8 vs. 30.6 months; P = .0190) than patients without LM. The significant difference in PFS was observed in both patients with EGFR exon 19 deletion (19del) and Leu858Arg mutation (L858R). However, patients with EGFR 19del and LM showed marginally significantly shorter OS ( P = .0531) and patients with EGFR L858R and LM had OS similar to that of patients without LM ( P = .1883). Regardless of EGFR status, patients with LM who received first-line chemotherapy had PFS and OS similar to those of patients without LM. Univariate analyses identified only never smoking (hazard ratio, 0.536; P = .012) was significantly associated with better OS for patients with NSCLC and LM. Conclusion EGFR mutation is not an independent risk factor for LM in NSCLC patients. However, the presence of LM is a negative predictive factor for first-line EGFR-TKI therapy for patients with EGFR-mutant NSCLC.

Background Bone morphogenetic protein 2 (BMP-2) is a member of the TGF-β superfamily that is closely correlated with many malignancies, particularly lung cancer. However, the effects of silenced BMP-2 on lung cancer cell proliferation and migration are not clear. Methods Using quantitative real-time RT-PCR, BMP-2 mRNA expression was detected in 61 non-small cell lung cancer (NSCLC) samples. Survival curves were generated using follow-up data. Relationships between clinical or pathological characteristics and prognosis were analyzed. Cell viability assays and transwell migration assays were used to evaluate the effects of BMP-2 silencing on cell proliferation and migration of A549 and H460 cells. Results BMP-2 mRNA expression was higher in NSCLC tissues compared to matched adjacent normal tissues (P