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Small-Cell Lung Cancer: Evidence to Date Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid

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Small-Cell Lung Cancer: Evidence to Date Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid Targeting the MET-Signaling Pathway in Non- Small-Cell Lung Cancer: Evidence to Date Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid To cite this version: Olivier Bylicki, Nicolas Paleiron, Jean-Baptiste Assié, Christos Chouaid. Targeting the MET-Signaling Pathway in Non- Small-Cell Lung Cancer: Evidence to Date. OncoTargets and Therapy, Dove Medical Press, 2020, Volume 13, pp.5691-5706. 10.2147/OTT.S219959. hal-02886104 HAL Id: hal-02886104 https://hal.sorbonne-universite.fr/hal-02886104 Submitted on 1 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Targeting the MET-Signaling Pathway in Non- Small–Cell Lung Cancer: Evidence to Date This article was published in the following Dove Press journal: OncoTargets and Therapy Olivier Bylicki 1,2 Abstract: The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, Nicolas Paleiron1 affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small–cell – Jean-Baptiste Assié2 4 lung cancer (NSCLC) is a potential therapeutic target. The development of high-output next- fi Christos Chouaïd2,3 generation sequencing techniques has enabled better identi cation of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth 1 Respiratory Disease Unit, HIA Sainte factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demon- Anne, Toulon, France; 2University Paris– Est Créteil (UPEC), CEpiA (Clinical strated the importance of MET amplification as an escape mechanism in patients with TKI-treated Epidemiology and Ageing), EA 7376- EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anoma- IMRB, UPEC, Créteil, France; fi 3Pneumology Department, Centre lies, trial results on METex14 alterations and MET ampli cationinnon-EGFRmutatedNSCLCs, Hospitalier Intercommunal De Créteil, andacquiredresistancetoTKIinEGFR-mutated NSCLCs. The outcomes of the first trials with 4 Créteil, France; Cordeliers Research anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were Center, Inserm, Functional Genomics of disappointing. Two situations seem the most promising today for the use of anti-METagents to treat For personal use only. Solid Tumors Laboratory, Sorbonne University, University of Paris, Paris, these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI- France EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation. Keywords: non-small–cell lung cancer, MET exon 14, MET amplification, MET pathway Introduction Targeted therapies have profoundly modified the prognoses of lung cancers with onco- genic mutations, achieving notably improved progression-free (PFS) and overall survival (OS) rates compared to reference chemotherapy regimens. That is particularly true for first- or second-line treatment of metastatic non-small–cell lung cancers (NSCLCs) OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 134.157.148.106 on 01-Jul-2020 harboring an epidermal growth factor-receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation.1–5 Targeted therapies have also shown their efficacy in patients carrying the v-RAF murine sarcoma viral oncogene homolog B (BRAFV600E) mutation, tyrosine-protein kinase-1 protooncogene (ROS1) or rearranged-during- transfection (RET) translocation.6–8 More recently, the efficacy of targeting the neuro- trophic tropomyosin receptor kinase (NTRK) in all patients whose cancers express it (making it a marker for tumor-agnostic therapy) was demonstrated.9 In other contexts, knowledge remains more fragmented, despite a potentially oncogenic target, with thera- pies having only modest activities. That is the case for NSCLCs expressing human Correspondence: Olivier Bylicki epidermal growth factor receptor-2 (HER2), Kirsten rat-sarcoma viral oncogene Respiratory Disease Unit, HIA Sainte (KRAS) or those with c-MET proto-oncogene (MET) protooncogene-pathway Anne, BRCM Toulon, 2, Boulevard Saint- 10–12 Anne, Toulon 83000, France abnormalities. Tel +33(0)483162937 The MET pathway was identified in the 1980s and its carcinogenic role in lung Fax +33(0)483162461 13,14 Email [email protected] cancer has been recognized since the 1990s. It is a complex pathway, poorly submit your manuscript | www.dovepress.com OncoTargets and Therapy 2020:13 5691–5706 5691 DovePress © 2020 Bylicki et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. – http://doi.org/10.2147/OTT.S219959 php and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Bylicki et al Dovepress understood, with anomalies, ranging from MET overex- Immunohistochemistry (IHC) is able to detect MET or pression, rare translocations, amplifications, de novo or HGF overexpression with several antibodies that are com- acquired under tyrosine-kinase inhibitors of epidermal mercially available. growth factor-receptor (EGFR) (EGFR-TKIs) and, finally, mutations, particularly of MET exon-14 (METex14) muta- Rearrangement tions. Numerous molecules targeting this pathway or its The first MET rearrangement was described in the 1990s with ligand, hepatocyte growth factor (HGF), are at various the tryptophan (TRP) gene.30 Other rearrangements have stages of development. since been found, notably in NSCLCs: kinesin family mem- This review summarizes the data available on our under- ber 5B (KIF5B), F-actin–capping proteins bind in a Ca2+ standing of the different molecular MET alterations, the (CAPZA2 (2)), cluster of differentiation 47 membrane pro- results obtained with agents targeting this pathway and the tein (CD47 (2)), testin (TES), caveolin-1 (CAV1), integrin contribution of immunotherapy to treating these patients.15,16 subunit alpha-9 (ITGA9), human leukocyte antigen (HLA- DRB1), transcription factor EC (TFEC), cortactin-binding The MET Pathway and Its protein-2 (CTTNBP2), ankyrin-1 (ANK1), steroidogenic acute regulatory-related lipid-transfer domain containing Alterations three N-terminal–like proteins (STARD3NL).31 The MET gene is located at 7q21–q31 on chromosome 7. 17,18 It is comprised of ~125 kb and 21 exons. MET is Amplification a heterodimer tyrosine-kinase receptor with extracellular, Amplification is an increased gene-copy number (GCN), transmembrane, juxtamembrane and kinase domains.19,20 linked to the focal duplication of a gene via breakage– MET binding to its exclusive ligand, HGF, leads to homo- fusion–bridge mechanisms.32 A higher GCN can also be dimerization and phosphorylation of the intracellular tyrosine secondary to polysomia of chromosome 7 (caused by chro- residues.18 Receptor activation stimulates downstream signal- mosomal duplication, for example).33,34 MET amplification For personal use only. ing pathways, such as extracellular signal-regulated kinase deregulates the METsignaling pathway by overexpression of (ERK)/mitogen-activated protein kinase (MAPK), phosphati- the protein and constitutive activation of kinases.33 The dylinositol 3-kinase-Akt (PI3K)/protein kinase B pathways number of MET copies can be evaluated by fluorescence and JAK/STAT (Janus kinase/signal transducer and activator in situ hybridization (FISH) or quantitative polymerase of transcription).20 Those pathways are known to be involved chain reaction. When using FISH, the MET/CEP7 (centro- in cell proliferation, migration, motility angiogenesis, survival meric portion of chromosome 7) ratio remains unchanged, and the epithelial-to-mesenchymal transition.21,22 whereas, with amplification, the MET GCN increases at the During embryogenesis, MET and HGF favor the for- expense of the number of centromeres, which results in mation of trophoblasts and placental hepatocytes.23 In a higher MET/CEP7 ratio.33 adults, the two proteins are strongly expressed in a wide New techniques of hybridization capture-based next- OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 134.157.148.106 on 01-Jul-2020 variety of tissues and can be regulated positively in generation sequencing (NGS) can analyze gene amplifica- response to a tissue lesion.18 tions. The GCN modifications can be identified by comparing Deregulation of the MET pathway in oncology can be tumor sequences in targeted regions to a normal diploid manifested in several ways: genetic mutation, amplifica- sample.35 Unlike FISH, NGS and multiplex
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