Glutathione (GSH)/GSH reductase (GSR) and thioredoxin/ thioredoxin reductase (TXNRD) are two major compensating thiol-dependent antioxidant pathways that maintain protein dithiol/disulfide balance. We hypothesized that functional deficiency in one of these systems would render cells dependent on compensation by the other system for survival, providing a mechanism-based synthetic lethality approach for treatment of cancers. The human GSR gene is located on chromosome 8p12, a region frequently lost in human cancers. GSR deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of GSR sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the GSR gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. GSR deficiency sensitized lung cancer cells to this agent. Analysis of a panel of 129 non-small cell lung cancer (NSCLC) cell lines revealed that auranofin sensitivity correlated with the expression levels of the GSR, glutamatecysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. In NSCLC patientderived xenografts with reduced expression of GSR and/or GCLC, growth was significantly suppressed by treatment with auranofin. Together, these results provide a proof of concept that cancers with compromised expression of enzymes required for GSH homeostasis or with chromosome 8p deletions that include the GSR gene may be targeted by a synthetic lethality strategy with inhibitors of TXNRD.Significance: These findings demonstrate that lung cancers with compromised expression of enzymes required for glutathione homeostasis, including reduced GSR gene expression, may be targeted by thioredoxin/thioredoxin reductase inhibitors.

Extra-nodal natural killer T-Cell (NK/T-cell) lymphoma is a progressive cancer with poor prognosis due to the lack of disease specific treatment. To develop specific therapeutic strategies, it is essential to identify tumor markers. Recent studies show that circulating microRNA (miRNA) may serve as diagnostic and/or prognostic markers for some diseases. To explore miRNAs as potential diagnostic and/or prognostic markers of NK/T-cell lymphoma, in our study, we compared circulating miR-221 levels in 79 patients and 37 normal subjects by real-time PCR amplification directly from plasma samples, and correlated patient's miR-221 levels with their clinic features and treatment outcomes. We observed a significant difference between the patient and control groups (p=0.038), and a correlation of plasma miR-221 level in patient with sex, as well as a reverse correlation with performance status and the overall survival after treatment. Univariate and multivariate analyses further revealed that plasma miR-221 level, age, B symptoms, LDH level and complete response after primary treatment all present prognostic values when judged by overall survival (OS). Together, our results show that it is feasible to perform direct amplification of plasma miRNAs without total RNA extraction, and plasma miR-221 may be a diagnostic and prognostic marker for NK/T-cell lymphoma.

Cisplatin is effective as a single agent or in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). A concerning clinical challenge with cisplatin-based NSCLC chemotherapy is the intrinsic and acquired chemoresistance to cisplatin. The sterile α motif domain-containing (SAMD9) gene has been reported as a potent tumor suppressor gene that inhibits tumorigenesis and progression of NSCLC. microRNAs (miRNA) have been revealed to play important roles in the regulation of cancer chemoresistance. To the best of our knowledge the present study explored the role of miRNA/SAMD9 signaling in regulating cisplatin chemoresistance in NSCLC for the first time. Out of the several candidate miRNAs predicted to bind the 3′-untranslated region (UTR) of the SAMD9 gene, miRNA-96 (miR-96) demonstrated significant target-sequence-specific inhibition of the SAMD9 3′-UTR luciferase reporter activity in NSCLC cells. In addition, while NSCLC tumor samples exhibited significantly higher expression levels of miR-96 compared with adjacent normal tissues, the expression levels of SAMD9 were significantly lower than those in adjacent normal tissues. miR-96 and SAMD9 were overexpressed and knocked down in the human NSCLC H358 and H23 cell lines and the half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. The present results identified that overexpression of miR-96 in NSCLC cells markedly decreased SAMD9 expression and cisplatin-induced apoptosis, and increased the cisplatin IC50, which could be eliminated by overexpression of SAMD9. By contrast, knocking down miR-96 in NSCLC cells using antagomir-96 significantly increased SAMD9 expression and the cisplatin-induced apoptosis and decreased cisplatin IC50, which could be completely reversed by a knockdown of SAMD9. In conclusion, the current study demonstrates that miR-96 targets and downregulates SAMD9 in NSCLC, which decreases cisplatin-induced apoptosis and induces cisplatin chemoresistance in NSCLC cells. The findings of the present study add novel insights into the function of miR-96 and SAMD9 in cancer, as well as into the molecular mechanisms underlying NSCLC chemoresistance.

Dacomitinib is a potent, irreversible and pan-HER tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). Currently, evidence of its activity on brain metastasis is lacking. Materials and methods: NSCLC patients diagnosed at Hunan Cancer Hospital between July, 2019 and July, 2020 with enhanced MRI-detected brain metastasis prior to treatment and laboratory-confirmed EGFR mutations were reviewed. In total, 14 EGFR-mutant NSCLC patients with brain metastasis were treated with first-line dacomitinib. The first radiographic review of chest CT and brain MRI was after one month and thereafter every 2 months. The objective response rate (ORR) and the depth of the brain metastasis response were determined via RECIST 1.1 and RANO-LM criteria. Results: In total, 14 of 59 EGFR-mutant advanced NSCLC patients who received first-line dacomitinib therapy had brain metastasis before treatment. Among these patients, 5 were given a dacomitinib starting dose of 45 mg once daily, while 9 received 30 mg daily until disease progression or unbearable toxicity. Eight patients harbored EGFR 19del, 5 had EGFR L858R, and one patient had EGFR G719A and I706 T co-mutations. The median duration of follow-up was 4.5 months. All patients received at least one review. The ORR was 92.9 % (13/14) and the disease control rate (DCR) was 100 %. A measurable response of the intracranial metastases was observed in 12 of 14 patients (85.7 %), including 12 of 13 (92.3 %) with brain parenchymal metastasis, but the one patient with meningeal metastasis did not respond well. All patients (100 %) had grade 1-2 adverse effects, but none discontinued treatment or required a dosage adjustment. Conclusions: This case series study of 14 patients has shown that dacomitinib has potent efficacy for central nervous system (CNS) metastasis in EGFR-positive NSCLC. More data are required to confirm its advantages and optimize its clinical application.