Detection of <i>EML4‐ALK</i> fusion genes in non‐small cell lung cancer patients with clinical features associated with <i>EGFR</i> mutations

Zhou, Shaozhang; Lin, Xiaobo; Zeng, Aiping; He, Jianbo; Song, Xiangqun; Qin, Yu

doi:10.1002/gcc.21976

Cited by 20 publications

(17 citation statements)

References 26 publications

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“…Previous studies have reported that EML4-ALK occurs at a significantly higher frequency in adenocarcinoma [5]–[7], [12], [15], [18], [19], while some studies have also reported that EML4-ALK occurs at a similar frequency in non-adenocarcinomas [8], [13], [14], [16], [17]. Our meta-analysis confirmed that EML4-ALK is significantly associated with adenocarcinoma.…”

Section: Discussionsupporting

confidence: 80%

Clinicopathologic Features of Patients with Non-Small Cell Lung Cancer Harboring the EML4-ALK Fusion Gene: A Meta-Analysis

Wang

et al. 2014

PLoS ONE

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BackgroundThe frequencies of EML4-ALK fusion gene in non-small cell lung cancer (NSCLC) with different clinicopathologic features described by previous studies are inconsistent. The key demographic and pathologic features associated with EML4-ALK fusion gene have not been definitively established. This meta-analysis was conducted to compare the frequency of the EML4-ALK fusion gene in patients with different clinicopathologic features and to identify an enriched population of patients with NSCLC harboring EML4-ALK fusion gene.MethodsThe Pubmed and Embase databases for all studies on EML4-ALK fusion gene in NSCLC patients were searched up to July 2014. A criteria list and exclusion criteria were established to screen the studies. The frequency of the EML4-ALK fusion gene and the clinicopathologic features, including smoking status, pathologic type, gender, and EGFR status were abstracted.ResultsSeventeen articles consisting of 4511 NSCLC cases were included in this meta-analysis. A significant lower EML4-ALK fusion gene positive rate was associated with smokers (pooled OR = 0.40, 95% CI = 0.30–0.54, P<0.00001). A significantly higher EML4-ALK fusion gene positivity rate was associated with adenocarcinomas (pooled OR = 2.53, 95% CI = 1.66–3.86, P<0.0001) and female (pooled OR = 0.61, 95% CI = 0.41–0.90, P = 0.01). We found that a significantly lower EML4-ALK fusion gene positivity rate was associated with EGFR mutation (pooled OR = 0.07, 95% CI = 0.03–0.19, P<0.00001). No publication bias was observed in any meta-analysis (all P value of Egger's test >0.05); however, because of the small sample size, no results were in the meta-analysis regarding EGFR gene status.ConclusionThis meta-analysis revealed that the EML4-ALK fusion gene is highly correlated with a never/light smoking history, female and the pathologic type of adenocarcinoma, and is largely mutually exclusive of EGFR.

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Section: Discussionsupporting

confidence: 80%

Clinicopathologic Features of Patients with Non-Small Cell Lung Cancer Harboring the EML4-ALK Fusion Gene: A Meta-Analysis

Wang

et al. 2014

PLoS ONE

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“…Therefore, it is important to develop a detection algorithm to fulfil this requirement and thus to efficiently select ALK translocated candidates for FISH analysis. Although EGFR mutations were detected in some of the NSCLCs with EML4‐ALK fusion genes, we did not detect any EGFR mutations in EML4‐ALK ‐positive patients. This phenomenon was the same as that seen in previous reports .…”

Section: Discussioncontrasting

confidence: 81%

Anaplastic lymphoma kinase translocation is correlated with anaplastic lymphoma kinase expression and mutually exclusive with epidermal growth factor receptor mutation in Taiwanese non‐small cell lung cancer

Hsu

Hung

Wang

et al. 2015

Pathology International

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The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is an important biomarker for target therapy. The aim of this study is to better understand the clinical and molecular features of the EML4-ALK fusion gene in lung cancer patients in Taiwan and therefore to generate an efficient algorithm for the detection of ALK translocation. In the first cohort, ALK translocation was identified in 1 adenocarcinoma from 100 lung cancer patients by using break apart fluorescent in situ hybridization (FISH). Next, we detected 6 ALK translocations in another 40 EGFR wild type adenocarcinomas but not in 40 cases with EGFR mutation. Histological analysis revealed that solid growth with signet-ring cells or cribriform glands with extracellular mucin were noted in all the 7 ALK translocated cases. One ALK positive cancer with mucinous cribriform pattern had no ALK expression. ALK expression was correlated with ALK translocation (p < 0.001), but not with ALK gene copy number gain (CNG) (P = 0.838). ALK translocation was also mutually exclusive with EGFR mutation in Taiwanese non-small cell lung cancer (P = 0.033). These results indicate that screening tests for EGFR mutation status and/or ALK expression could help efficiently select ALK translocated patients for target therapy.

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“…Our phosphoproteomics results show that phosphorylation of both EGFR and protein kinase C-δ (PKC-δ) was enhanced by crizotinib. Co-targeting both ALK and EGFR has resulted in enhanced ALK TKI therapeutic efficacy (43), and studies in human samples have identified increased EGFR phosphorylation as a potential mechanism of ALK inhibitor resistance (44). Recently, PKC-δ signaling was shown to confer resistance to ALK TKI alone; co-targeting of PKC and ALK has been shown to synergistically eliminate ALK-rearranged lung cancer cells (13).…”

Section: Resultsmentioning

confidence: 99%

Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

et al. 2016

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Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK kinase inhibitors but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between pro-survival and pro-apoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics. We identified a network of 464 proteins composed of subnetworks with differential response to ALK inhibitors. A small hairpin RNA screen targeting 407 proteins in this network revealed 64 and 9 proteins whose loss sensitized cells to crizotinib and alectinib, respectively. Among these, knocking down fibroblast growth factor receptor substrate 2 (FRS2) or coiled-coil and C2 domain-containing protein 1A (CC2D1A, both scaffolding proteins, sensitized multiple ALK fusion cell lines to the ALK inhibitors crizotinib and alectinib. Collectively, our data provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions, and identifies potential targets to improve the efficacy of ALK inhibitors in patients.

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Detection of EML4‐ALK fusion genes in non‐small cell lung cancer patients with clinical features associated with EGFR mutations

Cited by 20 publications

References 26 publications

Clinicopathologic Features of Patients with Non-Small Cell Lung Cancer Harboring the EML4-ALK Fusion Gene: A Meta-Analysis

Clinicopathologic Features of Patients with Non-Small Cell Lung Cancer Harboring the EML4-ALK Fusion Gene: A Meta-Analysis

Anaplastic lymphoma kinase translocation is correlated with anaplastic lymphoma kinase expression and mutually exclusive with epidermal growth factor receptor mutation in Taiwanese non‐small cell lung cancer

Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

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