Amplification and overexpression of <i><scp>CMET</scp></i> is a common event in brain metastases of non‐small cell lung cancer

Preusser, Matthias; Streubel, Berthold; Hainfellner, Johannes A.; Deimling, Andreas von; Widhalm, Georg; Dieckmann, Karin; Wöhrer, Adelheid; Hackl, Monika; Zielinski, Christoph; Birner, Peter

doi:10.1111/his.12475

Cited by 25 publications

(16 citation statements)

References 27 publications

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“…Activity of the cMET tyrosine kinase receptor has been shown to promote invasion and metastasis in NSCLC. 58,59 Furthermore, cMET overexpression was shown to promote survival and inhibit apoptosis in NSCLC cells. 60 More studies are needed to define the potential role of c-MET in AIR-induced invasiveness.…”

Section: Discussionmentioning

confidence: 99%

Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells

Oweida

Sharifi

Halabi

et al. 2016

Cancer Biology & Therapy

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Stereotactic ablative radiotherapy (SABR) has emerged as a highly promising treatment for medically inoperable early-stage non-small cell lung cancer patients. Treatment outcomes after SABR have been excellent compared to conventional fractionated radiotherapy (CFRT). However, the biological determinants of the response to ablative doses of radiation remain poorly characterized. Furthermore, there's little data on the cellular and molecular response of genetically distinct NSCLC subtypes to radiation. We assessed the response of 3 genetically distinct lung adenocarcinoma cell lines to ablative and fractionated ionizing radiation (AIR and FIR). We studied clonogenic survival, cell proliferation, migration, invasion, apoptosis and senescence. We also investigated the effect of AIR and FIR on the expression of pro-invasive proteins, epithelial-to-mesenchymal transition (EMT), extracellular signal-regulated kinases (ERK1/2) and the transmembrane receptor cMET. Our findings reveal that AIR significantly reduced cell proliferation and clonogenic survival compared to FIR in A549 cells only. This differential response was not observed in HCC827 or H1975 cells. AIR significantly enhanced the invasiveness of A549 cells, but not HCC827 or H1975 cells compared to FIR. Molecular analysis of pathways involved in cell proliferation and invasion revealed that AIR significantly reduced phosphorylation of ERK1/2 and upregulated cMET expression in A549 cells. Our results show a differential proliferative and invasive response to AIR that is dependent on genetic subtype and independent of intrinsic radioresistance. Further examination of these findings in a larger panel of NSCLC cell lines and in pre-clinical models is warranted for identification of biomarkers of tumor response to AIR.

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Section: Discussionmentioning

confidence: 99%

Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells

Oweida

Sharifi

Halabi

et al. 2016

Cancer Biology & Therapy

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“…Clinical trials need to establish whether inhibitors of target molecules such as EGFR, KRAS, BRAF, SMO, or PIK3C in patients with mutation-bearing brain metastases may be beneficial. Moreover, recent studies have detected relatively high frequencies of MET and FGFR gene amplifications in NSCLC BM and also inhibitors of these target aberrations should be studied in clinical investigations [15,27]. However, the design of such trials is not trivial and needs special consideration [28].…”

Section: Discussionmentioning

confidence: 99%

Spectrum of gene mutations detected by next generation exome sequencing in brain metastases of lung adenocarcinoma

Preusser¹,

Berghoff²,

Koller³

et al. 2015

European Journal of Cancer

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“…31,33,34,57,58). Amplification of MET (and overexpression of the protein) is also a common event in brain metastases of NSCLC (59). Furthermore, fluorescence in situ hybridization (FISH)-positive MET status predicts worse survival in patients with advanced NSCLC (56,60).…”

Section: Met Amplificationmentioning

confidence: 99%

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Salgia

2017

Molecular Cancer Therapeutics

130

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MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non-small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression, MET gene amplification, MET gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with MET-amplified or METoverexpressing NSCLC, and case studies or case series have shown that MET mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale. Mol Cancer Ther; 16(4); 555-65.Ó2017 AACR.

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Amplification and overexpression of CMET is a common event in brain metastases of non‐small cell lung cancer

Abstract: CMET overexpression and CMET amplification are commonly found in NSCLC BM and may represent a promising therapeutic target.

Cited by 25 publications

References 27 publications

Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells

Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells

Spectrum of gene mutations detected by next generation exome sequencing in brain metastases of lung adenocarcinoma

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

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