Identification of Metastasis-Associated Receptor Tyrosine Kinases in Non–Small Cell Lung Cancer

University of Cologne, Köln, North Rhine-Westphalia, Germany
Cancer Research (Impact Factor: 9.33). 04/2005; 65(5):1778-82. DOI: 10.1158/0008-5472.CAN-04-3388
Source: PubMed


Development of distant metastasis after tumor resection is the leading cause of death in early-stage non-small cell lung cancer (NSCLC). Receptor tyrosine kinases (RTK) are involved in tumorigenesis but only few RTKs have been systematically studied in NSCLC. Here, we provide quantitative real-time reverse transcription-PCR expression data of all RTKs (n=56) in primary tumors of 70 patients with early-stage (I-IIIA) NSCLC. Overall, 33 RTKs were expressed in at least 25% of the patients. Several RTKs were significantly expressed higher in tumors that ultimately metastasized. The hazard risk for metastasis development in stage I/II disease was increased at least 3-fold for tumors with high expression levels of insulin receptor, neurotrophic tyrosine receptor kinase 1, epidermal growth factor receptor, ERBB2, ERBB3, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1, or leukocyte tyrosine kinase. Relative risks were reduced 3-fold by expression of EPHB6 or DKFZ1. Three members of the epidermal growth factor receptor family were associated with a high risk of metastasis, emphasizing the validity of our data. High ERBB3 expression was significantly associated with decreased survival. Taken together, our genome-wide RTK expression map uncovered the previously unknown value of several RTKs as potential markers for prognosis and metastasis prediction in early-stage NSCLC. The identified RTKs represent promising novel candidates for further functional analyses.

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Available from: Sven Diederichs, Jan 09, 2014
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    • "In contrast, alterations in the expression of various PTKs, in their activation, and in the signaling molecules lying downstream of the receptors play important roles in the development of cancer [14,15]. PTK expression has been associated with poor prognosis and is a predictor of metastasis in NSCLCs [16]. Some PTKs, such as EGFR and human epidermal growth factor receptor (HER)2, play important roles in lung cancer and have emerged as targets of new drug therapies [17-19]. "
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    ABSTRACT: Background The expression of novel oncogenic kinase (NOK), a member of the protein tyrosine kinase (PTK) family, has been observed in several human malignancies including non-small cell lung cancer (NSCLC). However, the clinic relevance of NOK expression in NSCLC remains unclear. Methods In this study, NOK expression in tumor cells was assessed using immunohistochemical methods in 191 patients with resected NSCLC. The association of NOK expression with clinicopathological parameters, including the Ki-67 labeling index (LI), was also evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of NOK expression on survival. Results Data showed that NOK was expressed in 75.4% and 14.1% of cancer lesions and corresponding adjacent non-cancerous tissue, respectively. Out of all the clinicopathological factors analyzed, NOK expression was significantly correlated with the grade of tumor differentiation (P = 0.035), pTNM stage (P = 0.020), lymphatic metastasis (P = 0.005) and high Ki-67 LI (P < 0.001). NOK positive NSCLC patients had a significantly shorter survival time (P = 0.004, Log-rank test) and the prognostic significance of NOK expression was apparent in squamous cell carcinoma patients (P = 0.022). Multivariate analysis indicated that NOK expression may be an independent prognostic factor in NSCLC (hazard ratio [HR], 1.731; P = 0.043). Conclusions Our results indicate that NOK expression is of clinical significance and can serve as a prognostic biomarker in NSCLC.
    Full-text · Article · Jun 2014 · BMC Cancer
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    • "However, the cytoplasmic tail of HER3 contains six docking sites for the p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and serves as a scaffold for PI3K/protein kinase B signaling for the HER family via heterodimeric interactions with other HER family members [4–6]. Increased levels of HER3 have been associated with a negative clinical prognosis, including survival in several tumor types [7–11]. Recent data suggest that HER3 is involved in resistance to other HER receptor-targeted therapeutics, e.g., trastuzumab, lapatinib, cetuximab, gefitinib and erlotinib [12–16]. "
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    ABSTRACT: Patritumab (U3-1287) is a human epidermal growth factor receptor-3 (HER3)-targeted antibody that blocks ligand-associated activation of HER3. This open-label, phase 1 and dose-finding study ( Identifier: JapicCTI-101262) aimed to assess the safety, pharmacokinetics, incidence of anti-patritumab antibody, recommended dose for subsequent clinical studies, preliminary efficacy, and patritumab-related biomarkers in Japanese patients with advanced solid tumors. Patients received patritumab 9 or 18 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity occurred. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Dose-limiting toxicities (DLTs) were evaluated from the initial dose to Cycle 1 Day 21. Tumor response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Nine patients received patritumab 9 mg/kg (n = 3) or 18 mg/kg (n = 6). Five patients were male, all patients had Eastern Cooperative Oncology Group performance status (PS) ≤ 1, and median (range) age of 67 (50-69) years. No DLTs were reported. Patritumab-related AEs reported in ≥2 patients were ALT increase (three patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash maculo-papular and AST increase (two each). Pharmacokinetics profile was similar to the preceding US phase 1 study. Soluble HER3 concentration in serum unexpectedly increased in all patients. These changes did not correlate with clinical response. Four patients had a best response of stable disease. All patients tested had negative for anti-patritumab antibody formation. Patritumab was well tolerated up to 18 mg/kg without DLTs in Japanese patients with advanced solid tumors. Soluble HER3 increased in all patients.
    Full-text · Article · Jan 2014 · Cancer Chemotherapy and Pharmacology
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    • "Previously, we identified several human RTKs whose expression level correlated with the development of metastasis in early-stage NSCLC [20]. Whereas high mRNA expression of several RTKs was associated with an increased frequency of metastasis development, high mRNA expression levels of the two RTKs EPHB6 and DKFZ1 indicated a reduced risk for metastasis [20]. Recently, we identified EPHB6 as an epigenetically silenced metastasis suppressor in NSCLC, and expression of EPHB6 prevented metastasis formation in a xenograft metastasis model [21]. "
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    ABSTRACT: Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer. Here, we sequenced the entire coding region of EPHB6 in 80 non-small cell lung cancer patients and 3 tumor cell lines. Three potentially relevant mutations were identified in primary patient samples of NSCLC patients (3.8%). Two point mutations led to instable proteins. An in frame deletion mutation (del915-917) showed enhanced migration and accelerated wound healing in vitro. Furthermore, the del915-917 mutation increased the metastatic capability of NSCLC cells in an in vivo mouse model. Our results suggest that EPHB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer.
    Full-text · Article · Dec 2012 · PLoS ONE
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