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Targeting MET Dysregulation in Cancer

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Targeting MET Dysregulation in Cancer Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-19-1446 MINI REVIEW Targeting MET Dysregulation in Cancer Gonzalo Recondo 1 , Jianwei Che 2 , 3 , Pasi A. Jänne 1 , 4 , and Mark M. Awad 1 ABSTRACT Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplifi cation, mutation, rear- rangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specifi c, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers. signifi cance: Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance. INTRODUCTION as plexin–semaphorin–integrin (PSI) and the Ig-like, plexins, transcription factors (IPT) domains ( 9 ). Upon ligand binding, The MET proto-oncogene encodes the tyrosine kinase MET homodimerization results in the phosphorylation of key receptor of HGF and regulates embryogenesis, wound heal- intracellular tyrosine residues at positions Y1234/35 within ing, liver regeneration, angiogenesis, and immunomodula- the kinase domain and Y1349/56 in the docking site ( 10 ). tion, among other physiologic processes ( 1–5 ). In cancer, These events directly recruit downstream effectors including aberrant MET oncogenic signaling has been known to play a the SRC proto-oncogene and STAT3, as well as adaptor pro- role in promoting tumor invasion, angiogenesis, and metas- teins like the growth factor receptor–bound protein 2 (GRB2) tasis; however, the initial development of targeted thera- and SHC, leading to downstream activation of the MAPK pies against MET in unselected patient populations and and PI3K–AKT–mTOR pathways which promote cell migra- across different tumor types did not translate into improved tion, proliferation, and survival ( 9, 11 ). MET protein receptor clinical outcomes ( 1, 6–8 ). More recently, advances in the stability and degradation are regulated by the intracellular identifi cation of new biomarkers of MET dysregulation in juxtamembrane domain which is encoded in part by MET cancer have renewed immense interest in identifying MET- exon 14 and contains the tyrosine Y1003 residue that, when dependent malignancies and in developing effective treat- phosphorylated, serves as the binding site for the casitas B-lin- ment options. eage lymphoma (CBL) E3 ubiquitin ligase ( 12 ). CBL-mediated MET is a single-pass transmembrane receptor composed ubiquitination results in receptor internalization from the cell of an extracellular domain, transmembrane and juxtamem- membrane to endocytic vesicles and subsequent proteasomal brane domains, and a tyrosine kinase domain (TKD). The degradation ( 13, 14 ). Exon 14 in MET is 141 nucleotides long, extracellular portion of MET is the binding site for its ligand, spanning from nucleotides c.2888 to c.3028, corresponding HGF, and contains a semaphorin (SEMA) domain, as well to amino acids p.D963 to p.D1010 (NM_000245.2, variant 2). Of note, in an alternative splice isoform of MET which is 54 nucleotides longer (NM_001127500.2 Variant 1), exon 14 spans from nucleotides c.2942 to c.3082, corresponding to 1 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. 2 Department of Cancer amino acids p.D981 to p.D1028. This alternative numbering Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. 3 Depart- of nucleotides and amino acids has led to some confusion in ment of Biological Chemistry and Molecular Pharmacology, Harvard Medi- the literature. In this review, we will primarily use the shorter cal School, Boston, Massachusetts. 4 Belfer Center for Applied Cancer isoform (variant 2) when referring to MET sequences but will Science, Dana-Farber Cancer Institute, Boston, Massachusetts. indicate the corresponding sequence variant of the longer Corresponding Authors: Mark M. Awad, Dana-Farber Cancer Institute and isoform (variant 1). Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215. Phone: 617-632-3468; Fax: 617-632-5786; E-mail: [email protected]. The oncogenic role of MET was fi rst described with the edu ; and Pasi A. Jänne, Lowe Center for Thoracic Oncology, Dana-Farber discovery of the TPR–MET genomic rearrangement induced Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. Phone: 617- by the exposure of a nontumorigenic human osteogenic 632-6053; E-mail: [email protected] sarcoma cell line to the carcinogen N-methyl-N′-nitro-N- Cancer Discov 2020;10:922–34 nitrosoguanidine ( 15 ). Since then, across diverse tumor types, doi: 10.1158/2159-8290.CD-19-1446 multiple biological alterations in MET have been discovered ©2020 American Association for Cancer Research. including exon 14 skipping mutations, activating mutations 922 | CANCER DISCOVERY JULY 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 12, 2020; DOI: 10.1158/2159-8290.CD-19-1446 MET in Cancer MINI REVIEW ABMET MET MET kinase CDMET MET physiologic signaling exon 14 skipping domain mutations amplification fusions HGF Mutations P V1070E/R Fusion P P V1092I partners CBL binds to the Loss of H1094Y/R/L TPR juxtamembrane juxtamembrane H1124D HLA–DRB1 domain U U P P domain PP P P P P M1149T KIF5B PTPRZ1 U L1195F/V P P P U P P P P P STARD3NL F1200I P P Y1220I ST7 MET ubiquitination Impaired degradation D1228H/N and degradation Y1230C/D/H Extended signaling Increased MET expression and S1236R oncogenic signaling L1250T V1260L MET exon mRNA Exon 13 Exon 15 V1268T/I MET focal Chromosome 7 14 skipping amplification polysomy or copy-number gain Ligand-independent Constitutive kinase dimerization and Point mutations and deletions Exon 14 MET:CEP7 MET:CEP7 domain activation kinase activation in splicing regulatory sites ratio high ≠ ratio low Pre mRNA Exon 13 Exon 14 Exon 15 Downstream Downstream Intron 13 Intron 14 signaling signaling c.2888 c.3028 Figure 1. Mechanisms of MET oncogenic activation. A, MET activation is initiated after ligand binding of the HGF to the SEMA domain to the extracel- lular portion of the MET receptor, inducing receptor dimerization and phosphorylation of the intracellular domain leading to downstream signaling of several pathways. The E3 ubiquitin ligase CBL binds to reside Y1003 in the juxtamembrane domain (encoded in part by exon 14), resulting in receptor ubiquitination and degradation. MET exon 14 alterations including mutations or deletions in splicing regulatory sites, leading to exon skipping, deletion of a portion of the juxtamembrane domain, impaired CBL binding, decreased MET turnover, and ongoing oncogenic downstream pathway signaling. B, Point mutations in the TKD result in ligand-independent MET activation through autophosphorylation of the TKD, conveying sustained oncogenic downstream pathway signaling. C, Focal MET amplification leads to higher levels ofMET transcription and MET expression. MET amplification (high MET:CEP7 ratio) differs from chromosome 7 polysomy or copy-number gain in which the entire chromosome is duplicated (low MET:CEP7 ratio). Focal MET amplification, and consequently high MET expression, leads to enhanced ligand-independent oncogenic signaling by receptor autodimerization or oligomerization and autophosphorylation. D, Gene rearrangements involving the MET TKD result in fusion proteins that typically self-dimerize in a ligand-independent man- ner, leading to phosphorylation of the TKD. in the kinase domain, gene amplification, and protein overex- half-life of the MET receptor (Fig. 1A; ref. 18). As has been pression. Recognition and detection of these MET biomarkers described in some hereditary syndromes, point mutations in have fueled the clinical development of MET tyrosine kinase the last nucleotide of an exon often result in exon skipping inhibitors (TKI), antibodies, and antibody–drug conjugates (19), and point mutations in the last nucleotide of MET exon (ADC) aimed at targeting MET or its interactions with HGF 14 (c.3028 = c.3082; D1010X = D1028X in the shorter and or other binding partners. longer isoforms of MET, respectively) also tend to cause exon 14 skipping. Additional point mutations causing amino acid substitution of the Y1003 residue (= Y1021), such as Y1003C MOLECULAR MECHANISMS OF MET or Y1003F, are predicted to cause a similar biological effect ACTIVATION IN CANCER through loss of the CBL-binding site without causing exon 14 skipping (20). MET Exon 14 Alterations Splice-site and Y1003X mutations differ from other Approximately 3% of advanced non–small cell lung cancers mutations within exon 14, like T992I (= T1010I). The (NSCLC) harbor point mutations or deletions in MET exon oncogenic potential of this variant is controversial, as some 14 or its flanking introns which affect splicing sequences preclinical studies suggest that it imparts greater tumor including 5′- and 3′-splice sites, the branch-point adenosine, growth and invasion potential, whereas others report a or the polypyrimidine tract (12, 16, 17). These alterations lack of transforming
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