Cholesterol synthesis disruption combined with a molecule-targeted drug is a promising metabolic therapy for EGFR mutant non-small cell lung cancer.

BACKGROUND: Acquired resistance is a challenge for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. Here, we propose a novel treatment strategy based on recent lipid metabolism work. METHODS: We applied a variety of experimental methods such as immunoblotting, MTT, si-RNA, and animal models, to demonstrate the relationship between EGFR and low-density lipoprotein receptor (LDLR) and the effects of statin monotherapy, and TKI monotherapy, and their combination on cell proliferation at the cell level and animal level. RESULTS: LDLR has a positive correlation with EGFR, EGFR signaling upregulates LDLR expression through the SREBP-1 dependent pathway, EGFR mutation cells count on lipids to survive and grow. Combined with a molecule-targeted drug, atorvastatin not only enhances the treatment effect in vitro, but also mitigates the growth of NSCLC in vivo. In this animal experiment, the combination medicine (atorvastatin with TKI) has a better tumor suppression effect on NSCLC. In HCC827 cell line, the average tumor shrinkage is about 68% in Gefitinib group, and about 49% in atorvastatin group, but about 89% in combination group. In H1975 cell line, the average tumor shrinkage is about 18% in Osimertinib group, and about 8% in atorvastatin group, but about 44% in combination group. CONCLUSIONS: the combination of an EGFR-TKI and a statin for EGFR mutant NSCLC may be a novel tumor inhibiting treatment.

CD47 Overexpression Is Associated with Epstein-Barr Virus Infection and Poor Prognosis in Patients with Nasopharyngeal Carcinoma.

PURPOSE: Little is known about the clinical significance of CD47 expression and its association with Epstein-Barr virus (EBV) infection in patients with nasopharyngeal carcinoma (NPC). The aim of this study was to clarify the prognostic value and role of CD47 in EBV-associated NPC. MATERIALS AND METHODS: Sixty-six cases of non-metastatic NPC were retrospectively reviewed. Tissues were collected for immunohistochemical staining of CD47 and the EBV-encoded oncoprotein latent membrane protein 1 (LMP1). Western blotting and quantitative real-time PCR were performed to determine the CD47 and LMP1 levels in common human NPC cell lines. Additionally, CD47 and LMP1 expression in a constructed EBV-positive human NPC cell (CNE-2-EBV+) and a stable cell line transfected with LMP1 plasmid (CNE-2-LMP1) was assessed. Next, we used Western blotting to assess the decrease in CD47 expression on CNE-2-LMP1 cells after transfecting them with small interfering RNA (siRNA)-targeting LMP1. RESULTS: In NPC patients, CD47 overexpression was significantly associated with disease recurrence (P=0.010), leading to poorer disease-free survival (DFS; P=0.002) and overall survival (P=0.021). Multivariate Cox proportional hazards models demonstrated that CD47 (HR=5.452, P=0.016) was an independent prognostic factor of DFS. Moreover, CD47 expression was associated with plasma EBV-DNA copy number and LMP1 tissue expression. Among the human NPC cell lines, CD47 and LMP1 expression was notably higher in the EBV-positive C666-1 cell line than in the EBV-negative cell lines. Furthermore, EBV infection upregulated CD47 expression via LMP1-mediated pathways in human NPC cells. CONCLUSION: This study indicated that CD47 is related to EBV infection in NPC patients, and it is a feasible biomarker.

Tracking the important role of JUNB in hepatocellular carcinoma by single-cell sequencing analysis.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer, accounting for ~90% of all primary malignancy of the liver. Although various medical treatments have been used as systemic therapies, patient survival time may be extended by only a few months. Moreover, the underlying mechanisms of HCC development and progression remain poorly understood. In the present study, the single-cell transcriptome of one in vivo HCC tumor sample, two in vitro HCC cell lines and normal peripheral blood mononuclear cells were analysed in order to identify the potential mechanism underlying the development and progression of HCC. Interestingly, JunB proto-oncogene was identified to serve a role in the immune response and in development and progression of HCC, potentially contributing to the development of novel therapeutics for HCC patients.

miR-429 suppresses cell proliferation, migration and invasion in nasopharyngeal carcinoma by downregulation of TLN1.

BACKGROUND: miR-429 and TLN1 have been shown to affect the biological behaviours of many carcinomas. However, their effects in nasopharyngeal carcinoma (NPC) are not yet clear. Here, we investigated their regulatory relationships and effects on NPC cells. METHODS: TargetScan was used to predict the regulatory relationships of miR-429 and TLN1 in NPC cells. Then, Western blotting and quantitative real-time PCR (qPCR) were performed to examine TLN1 levels, and qPCR was used to determine miR-429 levels in NPC cell lines with different metastatic characteristics (5-8F, CNE-2, CNE-1, 6-10B and NP69), to investigate whether TLN1 and miR-429 are correlated with the metastatic characteristics of these cells. Next, we upregulated or downregulated miR-429 in 5-8F and 6-10B cells, which have different tumourigenicity and transferability, and examined TLN1 expression by western blotting and qPCR after transfection. QPCR was also performed to confirm successful transfection of miR-429 mimic into 5-8F and 6-10B cells. Dual luciferase reporter gene assay was performed to investigate whether miR-429 regulates TLN1 by binding to its 3'UTR. After transfection, Cell Counting Kit-8 (CCK8) and IncuCyte were used to examine the proliferation of these cells, and wound-healing assay, Transwell migration assay, and invasion assays were performed to investigate the changes in migration and invasion after transfection. RESULTS: Western blotting and qPCR analyses showed that the protein level of TLN1 was negatively correlated with miR-429 in NPC cell lines (P < 0.05), while the mRNA level showed no relation with miR429 expression (P > 0.05). In addition, cells with high transferability showed high TLN1 expression at the protein level, while miR429 expression showed the opposite trend (P < 0.05), but there were no differences at the mRNA level between the different cell lines. Overexpression of miR429 in 5-8F and 6-10B cells was accompanied by downregulation of TLN1 at the protein level (P < 0.05), while there were no significant differences at the mRNA level (P > 0.05). In addition, transferability, proliferation, and invasion were downregulated by miR429 overexpression (P < 0.05). However, dual-luciferase reporter gene assay indicated that TLN1 was not a direct target of miR-429. CONCLUSION: This study showed that miR-429 functions as a tumour suppressor in NPC by downregulation of TLN1, although the relationship is not direct.

The comparison of EGFR-TKI failure modes and subsequent management between exon 19 deletion and exon 21 L858R mutation in advanced non-small-cell lung cancer.

Background: Advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) might be distinct diseases. Therefore, it is necessary to take EGFR mutation subgroups into consideration for making choices of subsequent treatment after tyrosine kinase inhibitors (TKIs) failure. Patients and methods: 174 patients who developed to EGFR-TKI failure were categorized into three cohorts of dramatic progression, gradual progression and local progression. Chi-square was used to compare the distribution of failure modes between 19 Del and L858R. Kaplan-Meier method and Cox Regression were performed for analyses of survival in different subsequent treatments. Results: The distribution of EGFR-TKI failure modes showed no significant difference between 19 Del and L858R. Patients in gradual progression had a longer progression-free survival (PFS) and overall survival (OS) compared with other failure modes in whole population, 19 Del cohort and L858R cohort. 19 Del patients with dramatic progression would obtain survival benefit from chemotherapy, while those with gradual progression got no survival benefit neither from chemotherapy nor previous TKI continuation. However, patients with dramatic or gradual progression would benefit from previous TKI continuation in L858R cohort. Conclusion: For advanced EGFR-positive NSCLC patients with acquired resistance to EGFR-TKI, subsequent treatment should be personalized according to EGFR-TKI failure modes & EGFR mutation subtypes.

A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer.

Crizotinib has achieved astonishing success in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, no real-world studies described the clinicopathological characteristics and treatment of such patients in China. Patients were consecutively collected from Sun Yat-sen University Cancer Center. Chi-square test was applied to explore the relationship between ALK fusion status and metastasis sites. Kaplan-Meier methods and multivariable analyses were used to estimate progression-free survival (PFS). A total of 291 advanced NSCLC patients (ALK (+), N = 97; both ALK & epidermal growth factor receptor (EGFR) (-), N = 194) were enrolled. The occurrence of brain metastasis in ALK-positive patients was significantly higher than double-negative ones both at baseline (26.5% vs. 16.5%, P = 0.038) and during treatment (25.8% vs. 11.9%, P = 0.003), but opposite for pleural effusion (6.2% vs. 26.9%, P < 0.001 at baseline; 3.1% vs. 10.3%, P = 0.031 during treatment). ALK-positive patients of 53.6% used crizotinib, whereas others only received chemotherapy (37.1%) or supportive care (9.3%). Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs. 4.8 m, P < 0.001). ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC at any line. However, half advanced ALK-positive patients never received crizotinib, which was grim and need improving.

Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting: A Network Meta-Analysis.

Background: Neurokinin-1 receptor antagonists (NK-1RAs) are widely used for chemotherapy-induced nausea and vomiting (CINV) control in patients with highly emetogenic chemotherapy (HEC) and/or moderately emetogenic chemotherapy (MEC). Whether the efficacy and toxicity of antiemesis are different among various NK-1RA-based triple regimens is unknown. Methods: Data of complete responses (CRs) in the acute, delayed, and overall phases and treatment-related adverse events (TRAEs) were extracted from electronic databases. Efficacy and toxicity were integrated by pairwise and network meta-analyses. Results: Thirty-six trials involving 18 889 patients using triple regimens (NK-1RA+serotonin receptor antagonists [5HT3RA] + dexamethasone) or duplex regimen (5HT3RA+dexamethasone) to control CINV were included in the analysis. Different NK-1RA-based triple regimens shared equivalent effect on CRs. In patients with HEC, almost all triple regimens showed statistically significantly higher CRs than duplex regimen (odds ratio [OR]duplex/triple = 0.47-0.66). However, in patients with MEC, only aprepitant-based triple regimen showed better effect than duplex regimen statistically significantly in CRs (ORduplex/triple = 0.52, 95% confidence interval [CI] = 0.34 to 0.68). No statistically significant difference of TRAEs was found among different triple regimens. Palonosetron-based triple regimens were equivalent to first-generation 5HT3RAs-based triple regimens for CRs. Moreover, different doses of dexamethasone plus NK-1RA and 5HT3RA showed no statistically significant difference in CRs. Conclusions: Different NK-1RAs-based triple regimens shared equivalent effect on CINV control. Various triple regimens had superior antiemetic effect than duplex regimen in patients with HEC. Only aprepitant-based triple regimen showed better CINV control compared with duplex regimen in patients receiving MEC. Palonosetron and first-generation 5HT3RAs might share equivalent CINV control in the combination of NK-1RAs and dexamethasone. Lower doses of dexamethasone might be applied when used with NK-1RAs and 5HT3RAs.