MET Gene Copy Number Predicts Worse Overall Survival in Patients with Non-Small Cell Lung Cancer (NSCLC); A Systematic Review and Meta-Analysis

Dimou, Anastasios; Non, Lemuel; Chae, Young Kwang; Tester, William J.; Syrigos, Konstantinos

doi:10.1371/journal.pone.0107677

Cited by 49 publications

(32 citation statements)

References 32 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The prevalence of MET amplification is ~5% in untreated patients and 20% in those with acquired resistance to EGFR-TKIs (21–31). MET positivity via IHC and an increased MET gene copy number are both significantly associated with poor overall survival (21–24,32). Although some preclinical studies, phase I/II trials, and subgroup analyses of phase III trials of small molecules targeting MET (used either singly or in combination) for MET -amplified NSCLC have yielded favorable results, the efficacy of such agents has not yet been confirmed in large clinical trials (10,33–35).…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitors against MET-amplified non-small cell lung cancer

Chiba¹,

Togashi²,

Tomida³

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

show abstract

Section: Discussionmentioning

confidence: 99%

MEK inhibitors against MET-amplified non-small cell lung cancer

Chiba¹,

Togashi²,

Tomida³

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…60–63 This frequency depends on the antibody, assay, and the positivity cut-point. While MET protein expression has been associated with poor prognostic outcomes in lung cancer, 60, 64 it has thus far served as a poor predictive biomarker of response to targeted therapy.…”

Section: Met As a Co-driver In Nsclcmentioning

confidence: 99%

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Drilon

Cappuzzo

et al. 2017

Journal of Thoracic Oncology

321

277

View full text Add to dashboard Cite

The mesenchymal epithelial transition factor receptor (MET) is a potential therapeutic target in a number of cancers, including non-small cell lung cancer (NSCLC). In NSCLC, MET pathway activation is thought to occur via a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggest a role for MET activation as both a primary oncogenic driver in subsets of lung cancer, and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET exon 14 (METex14) alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers that are likely to be predictive of response. While previous trials that focused on MET pathway-directed targeted therapy in unselected or MET overexpressing NSCLC yielded largely negative results, more recent investigations focusing on METex14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.

show abstract

“…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). An analysis of OS based on MET FISH status-derived GCN revealed that increased GCN is an independent negative prognostic factor in surgically resected NSCLC, with OS of 25.8 months for patients with MET !5 copies/cell compared with 47.5 months for patients with MET <5 copies/cell (P ¼ 0.0045; ref.…”

Section: Met Amplificationmentioning

confidence: 99%

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Salgia

2017

Molecular Cancer Therapeutics

130

View full text Add to dashboard Cite

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.

show abstract

MET Gene Copy Number Predicts Worse Overall Survival in Patients with Non-Small Cell Lung Cancer (NSCLC); A Systematic Review and Meta-Analysis

Cited by 49 publications

References 32 publications

MEK inhibitors against MET-amplified non-small cell lung cancer

MEK inhibitors against MET-amplified non-small cell lung cancer

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Contact Info

Product

Resources

About