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Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer.

ABSTRACT: The underlying mechanisms for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in about 30%-40% of non-small cell lung cancer (NSCLC) patients remain elusive. Recent studies have suggested that activation of epithelial-mesenchymal transition (EMT) and type 1 insulin-like growth factor receptor (IGF1R) is associated with acquired EGFR-TKIs resistance in NSCLC. Our study aims to further explore the mechanism of EMT and IGF1R in acquired EGFR-TKIs resistance in NSCLC cell lines with mutant (PC-9) or wild-type EGFR (H460). Compared to parental cells, EGFR-TKIs-resistant PC-9/GR and H460/ER cells displayed an EMT phenotype and showed overexpression of IGF1R. SiIGF1R in PC-9/GR and H460/ER cells reversed EMT-related morphologies and reversed their resistance to EGFR-TKIs. Exogenous IGF-1 alone induced EMT in EGFR-TKIs-naïve PC-9 and H460 cells and increased their resistance against EGFR-TKIs. Inducing EMT by TGF-?1 in PC-9 and H460 cells decreased their sensitivity to EGFR-TKIs, whereas reversing EMT by E-cadherin overexpression in PC-9/GR and H460/ER cells restored their sensitivity to EGFR-TKIs. These data suggest that IGF1R plays an important role in acquired drug resistance against EGFR-TKIs by inducing EMT. Targeting IGF1R and EMT may be a potential therapeutic strategy for advanced NSCLC with acquired EGFR-TKIs resistance.

SUBMITTER: Zhou J

PROVIDER: S-EPMC4792560 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer.

Zhou Juan J Wang Jinjing J Zeng Yunyun Y Zhang Xi X Hu Qiaoting Q Zheng Jihua J Chen Bei B Xie Bo B Zhang Wei-Min WM

Oncotarget 20151201 42

The underlying mechanisms for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in about 30%-40% of non-small cell lung cancer (NSCLC) patients remain elusive. Recent studies have suggested that activation of epithelial-mesenchymal transition (EMT) and type 1 insulin-like growth factor receptor (IGF1R) is associated with acquired EGFR-TKIs resistance in NSCLC. Our study aims to further explore the mechanism of EMT and IGF1R in acquired EGFR-TKIs resis ...[more]

PMID: 26554308

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Project description:BACKGROUND:The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non-small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. METHODS:Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS:In total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR?=?1.88, 95%CI: 1.59-2.23, p <?0.001, I2 =?0.0%, P =?0.792) and overall survival (OS) (HR?=?1.92, 95%CI: 1.55-2.38, p <?0.001, I2 =?0.0%, P =?0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P <?0.001, I2 =?0.0%, P =?0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P <?0.001, I2 =?0.0%, P =?0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study. CONCLUSIONS:This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

Project description:BACKGROUND:Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations. METHODS:We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS. RESULTS:Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P?=?0.003 for PFS, and P?=?0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P?<?0.001). A Cox proportional regression model determined that PTEN deletion (HR?=?4.29,95% CI?=?1.72-10.70) and low PTEN expression (HR?=?1.96, 95% CI?=?1.22-3.13), MET FISH?+?(HR?=?2.83,95% CI?=?1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor. CONCLUSIONS:We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

Project description:BackgroundActivated epidermal growth factor receptor (EGFR) mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma EGFR mutation abundance, especially of the ultra-low abundance of EGFR mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear.MethodsWe qualitatively detected baseline EGFR status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of EGFR mutations through next-generation sequencing (NGS). Every 8-12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of EGFR sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant TP53 mutations, and clinical response to TKIs.ResultsThis prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for EGFR mutation-positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma EGFR mutation abundance was 0.1%, the ORRs of TKI-treated patients were significantly different (60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01-0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of EGFR sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant TP53 mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12-5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples.ConclusionsLiquid biopsy screening based on highly sensitive NGS is reliable for detecting drug resistance and actionable somatic mutations. The plasma abundance of the EGFR driver mutation affected clinical response to EGFR-TKIs in advanced NSCLC patients; prolongation of PFS was also observed in patients with an ultra-low abundance of EGFR sensitizing mutations.

Project description:Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been used for the first-line treatment of non-small cell lung cancer (NSCLC) and has shown good clinical effects. However, some patients fail to benefit from this treatment. The aim of this study is to analyze whether or not clinical-selected patients (Asian, adenocarcinoma histology, non-smoking) and EGFR mutation-selected patients benefit from EGFR-TKIs or chemotherapy. Our results could be used as basis to guide clinical therapy.Randomized controlled trials evaluating the efficacy of EGFR-TKIs versus chemotherapy as first-line treatments of NSCLC were obtained from electronic databases, namely, PubMed, Embase, American Society of Clinical Oncology (ASCO), European Society for Medical Oncology, and China Biology Medicine disc. Assessment, data collection, and statistical analysis were performed according to Cochrane Handbook 5.1.0.A total of 14 randomized controlled trials with 5,000 patients were included in this study. Compared with the chemotherapy group, EGFR-TKI therapy group in EGFR mutation-selected NSCLC patients showed a higher response rate (RR=2.31; 95%CI: 1.88-2.84) and more significant improvement in progression free survival (PFS; HR=0.39; 95%CI: 0.30-0.49); by contrast, no significant difference was observed in overall survival (OS; HR=0.99; 95%CI: 0.84-1.16). The response rate of clinical-selected patients treated with EGFR-TKI significantly increased (RR=1.30; 95%CI: 1.15-1.47) compared with that of the patients treated with chemotherapy; PFS (HR=0.93; 95%CI: 0.58-1.49) and OS (HR=0.91; 95%CI: 0.81-1.02) of the two groups did not significantly differ. Likewise, the PFS and the OS of the unselected patients in the EGFR-TKI treatment group and the chemotherapy group did not significantly differ, although the OS of the former was shorter than that of the latter.EGFR mutation-selected patients received more benefits from EGFR-TKI first-line treatment than other treatments. First-line EGFR-TKI treatment was recommended for clinically selected patients who were unsuitable for themotherapy. By comparison, first-line EGFR-TKI treatment was not a suitable choice for unselected patients.

Dataset Information

Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer.

Publications

Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer.

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