The METeoric rise of MET in lung cancer

Friedlaender, Alex; Drilon, Alexander; Banna, Giuseppe Luigi; Peters, Solange; Addeo, Alfredo

doi:10.1002/cncr.33159

Cited by 32 publications

(31 citation statements)

References 60 publications

(159 reference statements)

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“…MET amplification is also responsible for the 10-20% of the acquired resistance, especially to EGFR inhibitors, but also to ALK inhibitors, although METex14 mutations are also emerging as a resistance mechanism [7,8]. Alterations of METex14 are generally mutually exclusive with other primary oncogenic drivers, except for MET amplifications and copy number variants [9].…”

Section: Met 21 Epidemiologymentioning

confidence: 99%

“…The c-MET gene is a proto-oncogene located at chromosome 7q21-q31, which encodes for a heterodimer receptor tyrosine kinase (RTK), also known as hepatocyte growth factor receptor (HGFR), with extracellular, transmembrane, juxtamembrane, and kinase domains [9].…”

Section: Molecular Pathwaymentioning

confidence: 99%

“…The binding of MET to its ligand HGF leads to its homodimerization with subsequent auto-phosphorylation and activation of the intracellular tyrosine kinase domains. The activation of c-MET stimulates many downstream signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), mammalian target of rapamycin (mTOR), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways [9,16]. These pathways are involved in cell survival, proliferation, migration, invasion, angiogenesis, and the epithelial-to-mesenchymal transition.…”

Section: Molecular Pathwaymentioning

confidence: 99%

“…Since data on MET-inhibitors are rapidly expanding, here we mainly discuss the major therapeutic strategies, referring for details to dedicated reviews and clinical trials' results [5,[9][10][11].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…Other MET-TKIs are currently under evaluation in Phase II trials, including cabozantinib (NCT03911193, NCT01639508), merestinib (NCT02920996), bozitinib (NCT03175224, NCT04258033), and Glumetinib (NCT04270591) [9,10].…”

Section: Other Met-inhibitorsmentioning

confidence: 99%

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Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Rebuzzi

Zullo

Rossi

et al. 2021

IJMS

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In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

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Section: Met 21 Epidemiologymentioning

confidence: 99%

Section: Molecular Pathwaymentioning

confidence: 99%

Section: Molecular Pathwaymentioning

confidence: 99%

Section: Therapeutic Implicationsmentioning

confidence: 99%

Section: Other Met-inhibitorsmentioning

confidence: 99%

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Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Rebuzzi

Zullo

Rossi

et al. 2021

IJMS

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Molecular characterization ofMETfusions from a large real‐world Chinese population: A multicenter study

et al. 2023

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Purpose MET is a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under‐reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizing MET fusions in a large, real‐world Chinese cancer population. Methods We retrospectively included patients with solid tumors who had DNA‐based genome profiles acquired through targeted sequencing from August 2015 to May 2021. MET fusion‐positive (MET+) patients were subsequently selected for clinical and molecular characterization. Results We screened 79,803 patients across 27 tumor types and detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%–0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. High heterogeneity was observed for partners, with ST7, HLA‐DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence of TP53 in MET+ alterations, EGFR L858R, EGFR L861Q, and MET amplification. Conclusion To our knowledge, this is currently the largest study in characterizing MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.

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Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c‐Met to up‐regulate angiogenesis and lung adenocarcinoma growth

Kastana,

Ntenekou,

Mourkogianni

et al. 2023

Intl Journal of Cancer

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Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A 165 (VEGFA 165 ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1 À/À and Ptprz1 +/+ mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1 À/À lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1 +/+ LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1 À/À compared with Ptprz1 +/+ mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (β 3 ) integrin is decreased in Ptprz1 À/À LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1 À/À

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The METeoric rise of MET in lung cancer

Cited by 32 publications

References 60 publications

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Molecular characterization ofMETfusions from a large real‐world Chinese population: A multicenter study

Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c‐Met to up‐regulate angiogenesis and lung adenocarcinoma growth

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