microRNA-1321 and microRNA-7515 contribute to the progression of non-small cell lung cancer by targeting CDC20.

Cell division cycle 20 (CDC20) and microRNAs (miRNAs) are differentially expressed in non-small cell lung cancer (NSCLC). The current study aimed to investigate the role of miR-1321 and miR-7515 regulation in CDC20 during NSCLC development. CDC20 expression in paracancerous and tumor tissues was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The relationship between CDC20 expression and prognosis of patients was analyzed using the TCGA database. The expression profile of CDC20 in healthy lung cells and NSCLC cells was detected using qRT-PCR and western blotting. After the knockdown of CDC20 in NSCLC cells, the cell proliferation, apoptosis, migration, invasion, and cell cycle changes were investigated by CCK8, EdU, flow cytometry, wound healing, and Transwell assays. The miRNAs targeting CDC20 were predicted using two bioinformatics websites and validated using dual-luciferase assays. CDC20 was enhanced in NSCLC tissues and cells, thus predicting the poor prognosis in NSCLC patients. After CDC20 inhibition, the malignant phenotype of NSCLC cells was reverted. miR-1321 and miR-7515 targeted CDC20 and exhibited the same anti-tumor effects as CDC20 silencing. Functional rescue experiments showed that CDC20 overexpression averted the anti-tumor effects of miR-1321 and miR-7515 on NSCLC cells. miR-1321 and miR-7515 inhibited NSCLC development by targeting CDC20. Thus, the current study has implications in NSCLC treatment and provides novel insights into NSCLC management.

The relative and absolute benefit of programmed death receptor-1 vs programmed death ligand 1 therapy in advanced non-small-cell lung cancer: A systematic review and meta-analysis.

INTRODUCTION: Programmed death receptor-1 (PD-1) and its ligand (PD-L1) inhibitors have shown promising results in treating advanced non-small-cell lung cancer (NSCLC). Our objective was to compare the relative and absolute benefits between PD-1 and PD-L1 inhibitors in advanced NSCLC. MATERIALS AND METHODS: PubMed, EMBASE and the Cochrane Library were searched up to Dec 1, 2019, for randomized controlled trials of PD-1/PD-L1 inhibitors that had available overall survival (OS) data in NSCLC. Random-effects models were used to calculate the pooled estimates. RESULTS: Twenty-three randomized controlled trials (15,797 patients) of PD-1/PD-L1 inhibitors were included in the analysis. PD-1 inhibitors significantly extended OS compared with standard of care therapy (difference in means, 4.80 months, 95% CI 3.41-6.18; HR 0.72, 95% CI 0.66-0.78; P < 0.01 for both). PD-L1 inhibitors also significantly improved OS compared with standard of care therapy (difference in means, 2.59 months 95% CI 1.47-3.71; HR 0.83, 95% CI 0.79-0.88; P < 0.01 for both). More importantly, PD-1 inhibitors had significantly higher OS than PD-L1 inhibitors (difference in means, P = 0.015; HR, P = 0.006). The same increased OS benefit was observed in patients with PD-L1 ≥1% (P = 0.035) and PD-L1 <1% (P = 0.007). However, OS did not differ between PD-1 and PD-L1 inhibitors in patients with an EGFR mutation-positive status (P = 0.724) and who were never smokers (P = 0.999). CONCLUSIONS: PD-1 inhibitors showed superior relative and absolute OS benefits compared with PD-L1 inhibitors in the treatment of advanced NSCLC. These findings have implications for treatment selection in current clinical practice and future study design.

Association of PD-L1 expression status with the efficacy of PD-1/PD-L1 inhibitors and overall survival in solid tumours: A systematic review and meta-analysis.

Whether PD-L1-positive patients derive more overall survival benefit from PD-1/PD-L1 inhibitors in the treatment of advanced solid tumours is unclear. We systematically searched the PubMed, Cochrane library and EMBASE databases from January 1, 1966 to March 1, 2019, to identify randomised controlled trials of PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab) that had available hazard ratios (HRs) for death according to PD-L1 status. A random-effects model was used to calculate the pooled overall survival (OS) HR and 95% CI among PD-L1-positive and PD-L1-negative patients. An interaction test was performed to evaluate the heterogeneity between the two estimates. A total of 24 randomised trials, involving 12,966 participants, fulfilled the inclusion criteria. An OS benefit of PD-1/PD-L1 inhibitors was found in both PD-L1-positive patients (HR, 0.65; 95% CI, 0.60-0.70) and PD-L1-negative patients (HR, 0.82; 95% CI, 0.74-0.91) even at the minimum cut-off value of 1%. Significant differences in the efficacy of PD-1/PD-L1 inhibitors between PD-L1-positive and PD-L1-negative patients were noted at different cut-off values. Moreover, there was a positive dose-response relationship between PD-L1 positivity and OS benefit (HR for 1%, 0.58, [0.50, 0.67]; 5%, 0.52 [0.43, 0.64]; 10%, 0.50 [0.40, 0.63]). Subgroup analyses showed that these results were generally consistent, regardless of study design, line of treatment, treatment type, tumour type, PD-L1 staining cell type and median follow-up time. We demonstrated that PD-1/PD-L1 inhibitors significantly improved OS in both PD-L1 positive and PD-L1 negative patients compared to controls, but the magnitude of benefit was clinically PD-L1-dependent.

The prognostic value of PKM2 and its correlation with tumour cell PD-L1 in lung adenocarcinoma.

BACKGROUND: The prognostic value of PKM2 and its correlation with tumour cell PD-L1 in lung adenocarcinoma (LUAD) is unclear. METHODS: A total of 506 lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) dataset and 173 LUAD tumour tissues from Jiangxi Cancer Hospital were used to analyse the correlation between PKM2 and PD-L1 expression. We further established a stable LUAD cell line with PKM2 knockdown and confirmed the association via Western blotting and flow cytometry analysis. Moreover, the prognostic values of PKM2 and PD-L1 were evaluated by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Based on the above two large cohorts, we found that PKM2 was significantly positively associated with PD-L1 expression (r = 0.132, P = 0.003 and r = 0.287, P < 0.001, respectively). Subsequently, we found that PKM2 knockdown substantially inhibited PD-L1 expression in the A549 LUAD cell line. Moreover, survival analysis showed that higher expression of PKM2 was correlated with significantly shorter overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma patients (P < 0.001 and P = 0.050, respectively). Subgroup analysis showed that lung adenocarcinoma patients who expressed high PKM2 and PD-L1 levels experienced the poorest OS and DFS. Additionally, multivariate analysis suggested that high PKM2 and PD-L1 expression was an independent prognostic indicator for worse OS and DFS (HR = 1.462, P < 0.001 and HR = 1.436, P = 0.004, respectively). CONCLUSIONS: Our results demonstrated that PKM2 regulated PD-L1 expression and was associated with poor outcomes in lung adenocarcinoma patients.

Incidence of Ipilimumab-Related Serious Adverse Events in Patients with Advanced Cancer: A Meta-Analysis.

Background: Little is known about the incidence of ipilimumab-related serious adverse events (SAEs) across various tumor types, drug doses and treatment regimens. Methods: PubMed database was searched up to November, 2017 to identify prospective clinical trials of ipilimumab therapy for adult patients with cancer. Comparisons of the incidence were based on the χ2 test in univariate analysis and the logistic regression model in multivariate analysis. Results: Twenty-four studies (4549 patients) with 35 independent study cohorts (21 melanoma, 6 prostate cancer, 5 NSCLC, and 3 SCLC cohorts) of ipilimumab were included in the meta-analysis. The overall incidence of SAEs during ipilimumab mono-therapy was 26.1% (95% CI, 21.1%-31.8%). SAEs were more frequent in the 10 mg/kg groups than in the 3 mg/kg groups (35.9% vs 17.3%; P < 0.001). Combination therapy showed significantly higher incidence than mono-therapy in melanoma (33.8% vs 25.0%; P = 0.002). After adjustment for potential confounders, multivariable analyses demonstrated lower odds of SAEs in NSCLC (odds ratio [OR] 0.52, 95% CI 0.40-0.69, P < 0.001) and SCLC (OR 0.41, 95% CI 0.31-0.54, P < 0.001) compared with melanoma. The 10mg/kg cohort presented significantly higher odds than the 3mg/kg (OR 2.84, 95% CI 2.35-3.43, P < 0.001). The combination therapy showed significantly higher odds than the mono-therapy (OR 1.38, 95% CI 1.11-1.71, P = 0.003). Conclusions: The incidence of ipilimumab-related SAEs was higher in melanoma, the 10mg/kg group and during combination therapy. Clinicians should enhance awareness of these risk factors in clinical practice and carefully monitor patients.

Meta-analysis of incidence and risk of severe adverse events and fatal adverse events with crizotinib monotherapy in patients with ALK-positive NSCLC.

BACKGROUND: Numerous clinical trials show crizotinib has promising efficacy for anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients which trigger the substitution of traditional chemotherapy to be the current standard first-line treatment for these patients. Conversely, few reports systematically analyze toxicity of crizotinib. Hence, we performed a first meta-analysis to determine the risk of crizotinib-related severe adverse events (SAEs) and fatal adverse events (FAEs) in ALK positive NSCLC patients. MATERIALS AND METHODS: A systematic literature search was conducted through December 2016 to identify clinical trials that reported crizotinib monotherapy in ALK-positive NSCLC patients. Data on crizotinib-related SAEs and FAEs were extracted from each study and pooled to determine the overall incidence and risk. Random-effects or fixed-effects models were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs on basis of the heterogeneity of included studies. RESULTS: 1,924 patients from 11 clinical trials were included. The overall incidence of SAEs and FAEs with crizotinib was 19.9% (95% CI, 14.1% to 23.7%; P < 0.001) and 1.4% (95% CI, 0.9% to 2.1%; P < 0.001), respectively. Meanwhile, Asian patients have lower incidence of SAEs (11.5%, 95% CI: 7.9% to 16.5%). However, significant differences of SAEs (RR: 0.97, 95% CI, 0.79 to 1.18; P = 0.76) and FAEs (RR: 2.24, 95% CI, 0.49 to 10.30; P = 0.30) were not detected between crizotinib monotherapy and chemotherapy. CONCLUSIONS: Crizotinib may not increase the risk of SAEs and FAEs in patients with ALK positive NSCLC compared with chemotherapy.

Enhanced expression of PKM2 associates with the biological properties of cancer stem cells from A549 human lung cancer cells.

Cancer cells express the M2 isoform of glycolytic enzyme pyruvate kinase (PKM2) for favoring the survival under a hypoxic condition. Considering the relative low oxygen microenvironment in stem cell niche, we hypothesized that an enhanced PKM2 expression associates with the biological properties of cancer stem cells. We used A549 human lung cancer cell line and surgical resected lung cancer tissue samples from patients for experiments. We confirmed the co-localization of PKM2 and CD44, a popular marker for cancer stem cells in lung cancer tissue samples from patients. The expression of PKM2 was clearly observed in approximately 80% of the A549 human lung cancer cells. Remarkably, enhanced expression of PKM2 was specially observed in these cells that also positively expressed CD44. Downregulation of PKM2 in CD44+ cancer stem cells by siRNA significantly impaired the potency for spheroid formation, decreased the cell survival under fetal bovine serum deprivation and hypoxic conditions, but increased their sensitivity to anti-cancer drug of cisplatin and γ-ray. The enhanced expression of PKM2 seems to associate with the biological properties of cancer stem cells from A549 human lung cancer cells. Selective targeting of PKM2 may provide a new strategy for cancer therapy, especially for patients with therapeutic resistance.

Is there a benefit of first- or second-line crizotinib in locally advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer? a meta-analysis.

BACKGROUND: Crizotinib show a promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, differences in efficacy for first- and second-line crizotinib are unclear. RESULTS: The pooled overall response rate and progression-free survival were 65% and 9.38 months, respectively. In the subgroup analysis, first-line crizotinib showed a higher trend of overall response rate and longer trend of progression-free survival although there was no statistical difference between first-line and second-line crizotinib (74%, 11.28 months vs. 65%, 8.12 months, respectively; fixed effects model). Moreover, overall response rate between Asians and Caucasians were similar (67% and 66%, respectively; fixed effects model). MATERIALS AND METHODS: A comprehensive search of MEDLINE, EMBASE, WEB OF SCIENCE and the COCHRANE databases from their inception to February 2016 was performed to identify clinical trials in English-language journals. Pooled overall response rate, progression-free survival and differences between first- and second-line crizotinib were estimated. Moreover, overall response rate between Asians and Caucasians were also estimated. CONCLUSIONS: First-line crizotinib may more effective than second-line crizotinib for patients with locally advanced or metastatic ALK-positive NSCLC.