Tianqing Chu

Epidermal growth factor induces FoxO1 nuclear exclusion to activate MMP7-mediated metastasis of larynx carcinoma

The molecular mechanism underlying cancer invasiveness and metastasis of larynx carcinoma remains elusive. Here we reported a strong correlation between phosphorylated epidermal growth factor receptor (EGFR) and matrix metalloproteinase-7 (MMP7) levels in larynx carcinoma patients. To examine whether a causal link exists, we used a human larynx carcinoma line, Hep-2, to study the molecular basis of EGFR signaling and MMP7 activation. We found that EGF-induced EGFR phosphorylation in Hep-2 cells resulted in activation of MMP7 and, consequently, an increase in cancer invasiveness. An EGFR inhibitor efficiently blocked this EGF-induced activation of MMP7. Moreover, an inhibitor for PI3 kinase (PI3K)/Akt, but not an inhibitor for mitogen-activated protein kinase (MAPK) or an inhibitor for c-Jun N-terminal kinase (JNK), significantly inhibited the EGF-induced activation of MMP7, suggesting that PI3K/Akt signaling cascades may be responsible for EGF-activated MMP7. Further dissection of the pathway revealed that nuclear exclusion of Akt downstream target, FoxO1, was induced by EGF-induced Akt activation and could be inhibited by either the EGFR inhibitor or by the PI3K/Akt inhibitor. Expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP7 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI3K/Akt to induce FoxO1 nuclear exclusion, which activates MMP7 to promote larynx carcinoma metastasis. Thus, Akt and FoxO1 appear to be promising therapeutic targets for preventing the metastasis of larynx carcinoma.

Use of capture-based next-generation sequencing to detect ALK fusion in plasma cell-free DNA of patients with non-small-cell lung cancer.

Capture-based next-generation sequencing (NGS) is a potentially useful diagnostic method to measure tumor tissue DNA in blood as it can identify concordant mutations between cell-free DNA (cfDNA) and primary tumor DNA in lung cancer patients. In this study, the sensitivity, specificity and accuracy of capture-based NGS for detecting ALK fusion in plasma cfDNA was assessed. 24 patients with tissue ALK-positivity and 15 who did not harbor ALK fusion were enrolled. 13 ALK-positive samples were identified by capture-based NGS among the 24 samples with tissue ALK-positivity. In addition to EML4-ALK, 2 rare fusion types (FAM179A-ALK and COL25A1-ALK) were also identified. The overall sensitivity, specificity and accuracy for all cases were 54.2%, 100% and 71.8%, respectively. For patients without distant metastasis (M0-M1a) and patients with distant metastasis (M1b), the sensitivities were 28.6% and 64.7%, respectively. In the 15 patients who received crizotinib, the estimated median PFS was 9.93 months. Thus, captured-based NGS has acceptable sensitivity and excellent specificity for the detection of ALK fusion in plasma cfDNA, especially for patients with distant metastasis. This non-invasive method is clinically feasible for detecting ALK fusion in patients with advanced-stage NSCLC who cannot undergo traumatic examinations or have insufficient tissue samples for molecular tests.

EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China

INTRODUCTION There are a number of uncommon EGFR mutations whose associations with TKIs are not well clarified. Here, we summarize the clinical data of patients with multiple uncommon EGFR mutations and their sensitivity to EGFR TKIs. METHODS Between January 2009 and September 2014, we retrospectively examined stage IIIB/IV NSCLC patients harboring uncommon mutations in EGFR at the Shanghai Chest Hospital. RESULTS A total of 123 NSCLC patients harboring uncommon EGFR mutations with treatment and survival details were included in this analysis. 95 Patients who received therapy that consisted of EGFR TKIs experienced a significantly improved overall survival (OS) compared with those who did not receive EGFR TKIs (18.96 months, 95% CI, 16.65-21.26 vs 12.22, 95% CI, 9.17-15.27, p=0.017). The median progression-free survival (PFS) for patients who harbored the L861Q, G719X, 20ins, Del-19+L858R, Del-19 or L858R+T790M, and the Del-19 or L858R+other mutations were 8.90 months (95% CI, 4.47-13.34), 5.98 months (95% CI, 1.53-10.42), 2.00 months (95% CI, 0.00-5.41), 9.53 months (95% CI, 0.00-19.41), 1.94 months (95% CI, 0.00-4.43), and 9.79 months (95% CI, 0.73-18.85), respectively. The best objective response rates (ORRs) for patients who harbored L861Q, G719X, 20ins, Del-19+L858R, Del-19 or L858R+T790M, Del-19 or L858R+others were 46.7%, 42.9%, 8.3%, 71.4%, 22.2%, and 55.6%, respectively. CONCLUSIONS These results suggest that EGFR TKI therapy is effective in patients with L861Q/G719X/Del-19+L858R/Del-19 or L858R+other mutations; less effective in patients with 20ins/Del-19 or L858R+T790M.

Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation.

Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC.

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.

OBJECTIVE To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). METHODS A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. RESULTS A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (P<0.05). The symptom improvement rate was 57.3% (51/89), and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 (33.7%)] and diarrhea [15/89 (16.9%)]. The level of toxicity was typically low. CONCLUSIONS The use of icotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

NAD(P)H: Quinone oxidoreductase 1 (NQO1) C609T polymorphism and lung cancer risk: A meta-analysis.

No clear consensus has been reached on the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung cancer risk. We performed a meta-analysis to summarize the possible association. We conducted a computer retrieval of PubMed and Embase databases prior to May 2013. References of retrieved articles were also screened. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. According to the inclusion criteria, 25 articles (32 studies) were finally included. There was no statistical association between C609T polymorphism and lung cancer risk in overall, East Asians, African Americans, or Hispanics. In Caucasians, a significant association was found in allele comparison model (T vs. C) (P = 0.04, OR = 1.09, 95% CI 1.00–1.19, Pheterogeneity = 0.24, fixed-effects model). In the subgroup of squamous cell carcinoma, a borderline significance could be found in the dominant genetic model (TT + CT vs. CC) (P = 0.05, OR = 1.20, 95% CI 1.00–1.43, Pheterogeneity = 0.65, fixed-effects model). Significant association could also be found in allele comparison (T vs. C) (P = 0.03, OR = 1.21, 95% CI 1.01–1.44, Pheterogeneity = 0.68, fixed-effects model). In the subgroup of small cell lung cancer risk, significant association were found in allele comparison (T vs. C) (P = 0.03, OR = 1.68, 95%CI 1.05–2.68, Pheterogeneity = 0.10, random-effects model) and in the homozygote comparison (TT vs. CC) (P = 0.02, OR = 2.79, 95% CI 1.14–6.85, Pheterogeneity = 0.72, fixed-effects model). No association was observed in adenocarcinoma subgroup. Our study suggested that NQO1 C609T polymorphism might associate with lung cancer risk in Caucasians. This polymorphism might also associate with squamous cell carcinoma and small cell lung cancer risk.

Preoperative induction chemotherapy for resectable stage IIIA non-small-cell lung cancer: a meta-analysis of 13 double-blind, randomized clinical trials

BACKGROUND The role of Preoperative chemotherapy in patients with resected nonsmall-cell lung cancer (NSCLC) remains unclear, this study is aimed at evaluating the effectiveness of Preoperative chemotherapy in patients with resected non-small-cell lung cancer (NSCLC), by performing a meta-analysis of relevant trials. METHODS Searching the literature from MEDLINE, pubmed, OVID, The Cochrane library, Cancerlit, Clinicaltrials.gov, ASCO, ESMO and CBM database, a meta-analysis was carried out to compare patients with NSCLC receiving chemotherapy before surgery with those undergoing surgery alone. The odds ratio (OR) was estimated to assess the survival advantage of Preoperative chemotherapy. RESULTS Thirteen eligible randomized controlled trials (RCT) were identified, including 2561 patients, the meta-analysis showed preoperative chemotherapy improved survival with a OR of 0.80 (95% confidence interval, 0.68-0.94; P =0.008) in a subset analysis patients with IIIa stage also benefit from the preoperative chemotherapy. There was no evidence of statistical heterogeneity. CONCLUSIONS This analysis shows a significant benefit of preoperative chemotherapy and is currently the best estimate of the effectiveness of this therapy.

Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head‐to‐head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first‐line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression‐free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, p < 0.001) and 0.48 (95% CI, 0.29–0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.

Dynamics of EGFR mutations in plasma recapitulates the clinical response to EGFR-TKIs in NSCLC patients

Objectives Genomic profiling using plasma cell-free DNA (cfDNA) represents a non-invasive alternative to tumor re-biopsy, which is challenging in clinical practice. The feasibility of dynamically monitoring epidermal growth factor receptor (EGFR) mutation status using serial plasma samples from non-small cell lung cancer (NSCLC) patients treated by tyrosine kinase inhibitors (TKIs) and its application in tracking clinical response and detection of resistance were investigated. Patients and methods Forty-five NSCLC patients with EGFR mutation-positive pre-TKI plasma and at least two post-TKI plasma collections were recruited to this study. EGFR mutations including L858R, exon 19 deletion (19-del) and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples. Results We observed a significant reduction in plasma EGFR mutation abundance during the first two-month of TKI treatment. Acquiring of secondary T790M gatekeeper mutation or completed “loss” of EGFR mutations represented two major categories of resistance profiles. Moreover, we demonstrated that levels of plasma EGFR mutations highly correlated with changes of tumor diameter as determined by radiographic imaging, or development of new lesions. In a subset of patients, we further showed that reappearance of EGFR mutations could be detected in plasma up to 5 months ahead of progressive disease (PD), suggesting an early detection of drug resistance. Conclusions Our findings suggest that genomic analysis using plasma cfDNA may offer an effective approach to monitor clinical response and emergence of resistance.

Serum dickkopf-1 as a clinical and prognostic factor in non-small cell lung cancer patients with bone metastases

Background The study was designed to evaluate the association between serum dickkopf-1 (DKK1) and non-small cell lung cancer (NSCLC) bone metastases. Materials and Methods Serum DKK1 levels were quantified in 470 NSCLC patients, 140 with osseous metastases, 178 with extraosseous metastases, and 152 with early stage in complete remission. The Receiver Operating Characteristic (ROC) curve enabled us to identify a threshold value to distinguish patients with bone metastases. Results Serum DKK1 levels in patients with osseous metastases were significantly higher than in the other 2 groups (P < 0.001). ROC curves showed that the optimum cutoff was 311.8 pg/ml (area under curve 0.791, 95% confidence interval 0.739–0.843, sensitivity 77.1% and specificity 71.4%). Of interest, serum DKK1 correlated with the number of bone lesions (P = 0.042) and associated with the poor survival in NSCLC patients with osseous metastases (P = 0.029). Conclusions Our data shows that serum DKK1 can be used for the detection of NSCLC bone metastases. More importantly this is the first report to show that serum DKK1 is a good predictor of poor prognosis in NSCLC patients with bone metastases.BACKGROUND The study was designed to evaluate the association between serum Dickkopf-1(DKK1)and non-small cell lung cancer(NSCLC) bone metastases. MATERIALS AND METHODS Serum DKK1 levels were quantified in 470 NSCLC patients, 140 with osseous metastases, 178 with extraosseous metastases, and 152 with early stage in complete remission. The Receiver Operating Characteristic (ROC) curve enabled us to identify a threshold value to distinguish patients with bone metastases. RESULTS Serum DKK1 levels in patients with osseous metastases were significantly higher than in the other 2 groups (P < 0.001). ROC curves showed that the optimum cutoff was 311.8 pg/ml (area under curve 0.791, 95% confidence interval 0.739-0.843, sensitivity 77.1% and specificity 71.4%). Of interest, serum DKK1 correlated with the number of bone lesions (P = 0.042) and associated with the poor survival in NSCLC patients with osseous metastases (P = 0.029). CONCLUSIONS Our data shows that serum DKK1 can be used for the detection of NSCLC bone metastases. More importantly this is the first report to show that serum DKK1 is a good predictor of poor prognosis in NSCLC patients with bone metastases.