Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L et al.. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104: 20932-20937

Human Oncology and Pathogenesis Program, Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(52):20932-7. DOI: 10.1073/pnas.0710370104
Source: PubMed


In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

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    • "We then evaluated the presence of gene amplification, since an increased MET copy number has already been described as a mechanism of resistance to small kinase inhibitors (Bean et al., 2007; Cepero et al., 2010a; Engelman et al., 2007). As illustrated in Figure 3A, EBC1 resistant cells presented a significant increase of MET copies (from 24 e as observed in parental cells e to 30), that was approximately 15-fold that of diploid cells (Lutterbach et al., 2007). "
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    ABSTRACT: The relevant role in cancer played by the tyrosine kinase receptor encoded by the MET oncogene led to the development of specific inhibitors, some of which are now in advanced phases of clinical trials. Previous experience has shown that the main limit to the efficacy of most targeted treatments is the advent of resistance. Mechanisms underlying resistance to MET-specific small tyrosine kinase inhibitors (TKIs) have been already described, while nothing is known about resistance to MET monoclonal antibodies, nor about bypassing resistance to chemical TKIs by antibodies or vice-versa. EBC1 lung cancer cells are MET-addicted as a consequence of gene amplification and thus sensitive to MET inhibitors, including the monovalent form of a MET monoclonal antibody (MV-DN30). We generated cells resistant to this antibody and found that resistance was due to a further increase of gene copy number and a dramatic overexpression of the MET receptor. Such an excess of expression saturated the ‘shedding’ activity of MV-DN30, and prevented both the efficient down-regulation of the MET receptor from the surface and the inhibition of the ensuing constitutive activation. Notably, antibody-resistant cells remained MET-‘addicted’ and were still sensitive to MET TKIs. Moreover, antibody-resistant cells became ‘drug-dependent’, since the removal of MV-DN30 led them to death due to excess of signal. In the mirror experiment, cells made resistant to MET-specific TKIs were still sensitive to treatment with the antibody MV-DN30. These findings suggest that a discontinuous, combined treatment by antibodies and chemical kinase inhibitors may increase the clinical response and bypass resistance to anti-MET targeted therapies.
    Molecular Oncology 12/2014; 8(8). DOI:10.1016/j.molonc.2014.06.010 · 5.33 Impact Factor
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    • "An association between MET copy gains and a worse prognosis in patients with NSCLC has been found previously [6] [7] [8] [9], but the data are limited and inconsistent. Recently, an increase in MET copy number (CN) has been demonstrated to be responsible for about 20% cases of the acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC [10] [11], suggesting that, as a pre-existing condition occurring before treatment, it may provide a primary lack of response [12], although a number of researchers deny that possibility [10] [13]. The rate of MET copy gain in NSCLC reported thus far ranges significantly from 3% to 21% depending on the detection technique used [6,7,14–17] and patient cohort differences [15]. "
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    ABSTRACT: The aim of the present study was to investigate the relationship of MET copy number (CN) and MET mRNA expression to other molecular alterations, clinicopathologic characteristics, and survival of patients with resected non–small cell lung cancer. One hundred fifty-one paired surgical samples of tumor and tumor-distant normal lung tissues were analyzed by comparative quantitative polymerase chain reaction (PCR) methods with commercially available assays and the CopyCaller software v. 1.0 for post-PCR data processing (downloadable from MET copy gain (set as more than 3.0 copies per cell) was found in 18.5% of the samples and occurred more frequently in the adenocarcinomas (ADCs) with an increased epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) CN (P = .001 and .030 for EGFR and HER2, respectively) and in the ADCs with EGFR activating mutations (P = .051) but did not correlate with KRAS dosage or mutational status. MET mRNA level was 1.76-fold higher [95% confidence interval (CI), 1.29-2.40] in the tumor compared to unaffected lung tissue and associated significantly with MET CN (beta coefficient, 1.51; 95% CI, 1.22-1.87; P < .001). In the multivariable analysis, patients diagnosed with ADC with increased MET CN had a significantly higher risk of disease recurrence (hazard ratio, 1.76; 95% CI, 1.20-2.57; P = .004). An increased MET CN in combination with histologic type appears to be a prognostic factor in patients with ADC after a curative surgery.
    Translational oncology 10/2014; 7(5):605–612. DOI:10.1016/j.tranon.2014.08.002 · 2.88 Impact Factor
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    • "Some mechanisms of acquired resistance to EGFR-TKIs have been identified, such as MET amplification, small-cell histologic transformation, and HER2 amplification.82–84 However, the p.T790M mutation is the most prevalent mechanism. "
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    ABSTRACT: Non-small-cell lung cancer (NSCLC) has entered the age of individual treatment, and increasing point mutations of specific oncogenes and rearrangement of some chromosomes are biomarkers used to predict the therapeutic effect of targeted therapy. At present, there is a consensus among clinicians that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown favorable efficacy in NSCLC patients with EGFR mutation, and some relevant research has suggested that the presence of EGFR mutations is a favorable prognostic marker. However, the association of EGFR mutation status with the responsiveness to conventional chemotherapy agents and survival in NSCLC patients is still unclear. This review provides an overview of and assesses the role of EGFR as a prognostic marker for postoperative patients and as a predictive marker for response to cytotoxic chemotherapy. In addition, we review the comparison of response to chemotherapy between EGFR mutations in exon 19 and in exon 21 and the predictive role of p.T790M mutation.
    Drug Design, Development and Therapy 09/2014; 8:1595-1611. DOI:10.2147/DDDT.S69690 · 3.03 Impact Factor
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