# MET Receptor Tyrosine Kinase: Exon 14 Skipping Mutations, HGF Ligand Activation, and Targeted Inhibitors


## Key Takeaways

- MET exon 14 skipping mutations, arising from aberrant splicing, lead to a constitutively active receptor tyrosine kinase by deleting the juxtamembrane domain responsible for ubiquitin-mediated degradation, a critical oncogenic driver in approximately 3-4% of non-small cell lung cancer (NSCLC).
- MET gene amplification is a significant oncogenic driver and a common mechanism of acquired resistance to EGFR TKIs in NSCLC, activating bypass signaling pathways such as PI3K/AKT.
- Targeted therapies, including FDA-approved ATP-competitive inhibitors like capmatinib and tepotinib, demonstrate substantial efficacy in NSCLC patients with MET exon 14 skipping mutations, achieving objective response rates of 40-68%.
- MET signaling is tightly regulated by negative feedback mechanisms, including c-Cbl-mediated ubiquitination and degradation, and its dysregulation is implicated in various cancers, neurodevelopmental disorders (e.g., autism spectrum disorder via promoter variants), and viral infections.
- Resistance to MET inhibitors can manifest through on-target mutations in the kinase domain or off-target activation of bypass pathways, necessitating combination strategies involving MET inhibitors and other targeted agents.

---

## Executive Summary & Key Metadata

The **MET** gene (MNNG HOS Transforming Gene) encodes a high-affinity receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF), also known as scatter factor (SF). MET is a prototypical member of the RTK family, characterized by a unique heterodimeric structure and a multifunctional role in embryogenesis, tissue regeneration, and cancer progression [1, 2]. The receptor is essential for epithelial-mesenchymal interactions during development, and its dysregulation—through mutation, amplification, overexpression, or aberrant splicing—is a hallmark of multiple solid tumors [3, 4, 5].

The clinical relevance of MET has expanded dramatically with the discovery of **exon 14 skipping mutations** in non-small cell lung cancer (NSCLC), which result in a constitutively active receptor lacking the juxtamembrane (JM) domain responsible for ubiquitin-mediated degradation [4, 6, 7]. This alteration, alongside high-level gene amplification, defines a targetable oncogenic subset of tumors. The development of selective small-molecule inhibitors (e.g., capmatinib, tepotinib) and monoclonal antibodies has transformed the therapeutic landscape for MET-driven malignancies [7, 8, 9].

This reference manual provides a comprehensive, biophysically detailed analysis of the MET gene and protein, covering genomic organization, structural biology, signaling pathways, pathogenic mutations, [pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), and bioinformatic resources.

| **Attribute** | **Value** |
|:---|:---|
| **HGNC Symbol** | MET |
| **UniProt Accession** | P08581 |
| **Representative PDB ID** | 2RFS (Crystal structure of the MET kinase domain in complex with a selective inhibitor) |
| **Chromosomal Locus** | 7q31.2 (GRCh38: chr7:116,672,196-116,798,386) |
| **Primary Molecular Function** | Receptor tyrosine kinase; HGF binding; activation of RAS/MAPK, PI3K/AKT, JAK/STAT, and PLCγ pathways |
| **Disease & Pathology Associations** | Non-small cell lung cancer (exon 14 skipping, amplification), gastric cancer, hepatocellular carcinoma, glioblastoma, autism spectrum disorder (promoter variants), Rett syndrome, papillary renal cell carcinoma (hereditary) |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Gene Coordinates and Architecture

The human *MET* gene is located on the long arm of chromosome 7 at cytoband **7q31.2**. The genomic span is approximately 126 kb, oriented on the minus strand of the reference genome (GRCh38). The gene comprises **21 exons** and **20 introns**, with the coding sequence distributed across exons 2 through 21. Exon 1 is non-coding and contains the core promoter and 5' untranslated region (UTR) [4, 7].

The intron-exon boundaries are highly conserved across mammals. Notably, **exon 14** encodes the juxtamembrane (JM) domain, a critical negative regulatory region containing the Y1003 residue (c-Cbl E3 ubiquitin ligase binding site) and the serine residue S985 (protein kinase C phosphorylation site). The intronic splice donor and acceptor sites flanking exon 14 are hotspots for mutations that cause exon skipping [4, 6, 7].

### 1.2 Promoter Architecture and Transcription Factor Binding

The *MET* promoter is a TATA-less, GC-rich region containing multiple Sp1 binding sites. The most extensively studied polymorphism is **rs1858830**, a C/G single nucleotide variant located in the promoter region approximately 2 kb upstream of the transcription start site. The C allele ("low activity" allele) reduces promoter activity by disrupting a consensus binding site for the transcription factor **Sp1** and the transcriptional regulator **SUB1** [1, 2, 3]. This variant is associated with reduced MET protein expression in the brain and is a replicated risk factor for autism spectrum disorder (ASD) [1, 2, 3, 4].

Additional transcription factors regulating *MET* expression include:
- **PAX6/PAX6(5a)**: The alternatively spliced PAX6(5a) isoform directly transactivates the *MET* promoter in pancreatic cancer cells, contributing to MET overexpression [5].
- **MeCP2**: Methyl-CpG-binding protein 2 (MeCP2) binds to the *MET* promoter and regulates its expression. Loss of MeCP2 function, as seen in Rett syndrome, leads to altered MET expression with sex-specific effects [2].
- **ETS family members**: ETS transcription factors (e.g., ETS1, ELK1) bind to the promoter in response to RAS-MAPK signaling, creating a positive feedback loop [4].

### 1.3 Enhancer Elements and Chromatin State

Chromatin immunoprecipitation (ChIP)-seq data from ENCODE reveal multiple enhancer-associated histone marks (H3K27ac, H3K4me1) within the *MET* locus, particularly in intronic regions and downstream of the 3' UTR. These enhancers are cell-type specific, with active enhancers in epithelial cells and cancer cell lines but not in hematopoietic cells. The three-dimensional chromatin architecture places the *MET* promoter in proximity to enhancers located in the neighboring gene *CAPZA2* and the long non-coding RNA *METTL15* [4, 7].

### 1.4 Alternative Splicing and Isoforms

Alternative splicing generates multiple MET transcript variants:

1. **Full-length MET (isoform 1)**: The canonical 1390-amino acid (aa) precursor protein (UniProt P08581-1). This is the predominant, functional isoform.
2. **Exon 14 skipping isoform**: A 1355-aa variant lacking the JM domain. This isoform is constitutively active due to loss of the c-Cbl binding site (Y1003) and the PKC phosphorylation site (S985). It is the oncogenic driver in MET exon 14-altered cancers [4, 6, 7].
3. **Novel skeletal muscle isoform (Met-SM)**: A splice variant identified in human skeletal muscle that lacks a portion of the extracellular domain. This isoform acts as a dominant-negative inhibitor of HGF/MET signaling and promotes myogenic differentiation [6].
4. **Soluble MET (sMET)**: Generated by proteolytic cleavage of the extracellular domain by metalloproteases (ADAM10/17) or by alternative splicing producing a secreted form. sMET can sequester HGF and act as a decoy receptor [4].

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization

The MET receptor is synthesized as a single-chain 170 kDa precursor (pro-MET), which is proteolytically cleaved by furin into a disulfide-linked heterodimer consisting of an extracellular α-chain (50 kDa) and a transmembrane β-chain (145 kDa) [1, 5]. The mature receptor spans 1390 amino acids with the following domain architecture:

| **Domain** | **Residues (approx.)** | **Function** |
|:---|:---|:---|
| **Signal peptide** | 1-24 | Directs co-translational translocation to the ER |
| **Sema domain** | 25-515 | β-propeller structure; HGF binding; receptor dimerization |
| **PSI domain** | 516-561 | Plexin/semaphorin/integrin homology; cysteine-rich; structural linker |
| **IPT domains (4x)** | 562-924 | Immunoglobulin-like, plexin, transcription factor domains; HGF binding; ligand specificity |
| **Transmembrane helix** | 925-945 | Single-pass membrane anchor |
| **Juxtamembrane domain** | 946-1000 | Negative regulation; contains Y1003 (c-Cbl site) and S985 (PKC site) |
| **Tyrosine kinase domain** | 1001-1345 | Catalytic activity; ATP binding; autophosphorylation |
| **C-terminal tail** | 1346-1390 | Docking sites for adaptor proteins (Y1349, Y1356) |

### 2.2 Extracellular Domain Structure

The extracellular region adopts a highly organized architecture critical for ligand binding and receptor activation:

- **Sema domain**: The N-terminal Sema domain forms a seven-bladed β-propeller structure. This domain is the primary HGF binding site and is essential for receptor dimerization. The Sema domain also contains a cysteine-rich region that forms a "cysteine knot" motif [1, 5].
- **PSI domain**: A small, cysteine-rich domain that connects the Sema domain to the IPT domains. It contributes to the structural rigidity of the extracellular region.
- **IPT domains**: Four immunoglobulin-like domains (IPT1-4) that extend the receptor above the cell surface. IPT3 and IPT4 are involved in HGF binding specificity, particularly for the HGF β-chain [1, 5].

### 2.3 Intracellular Kinase Domain Structure

The tyrosine kinase domain (residues 1001-1345) adopts the canonical bilobed architecture of protein kinases:

- **N-lobe**: Contains a five-stranded β-sheet and the αC-helix. The ATP-binding pocket is formed between the N-lobe and the hinge region.
- **C-lobe**: Contains the activation loop (A-loop), the catalytic loop (HRD motif), and the substrate-binding region.
- **Activation loop**: The A-loop contains the critical residues Y1234 and Y1235, which are the primary autophosphorylation sites. Phosphorylation of these residues stabilizes the active conformation of the kinase [7].

The crystal structure of the MET kinase domain (PDB: 2RFS) reveals the DFG motif (D1222-F1223-G1224) at the N-terminus of the A-loop, which coordinates Mg²⁺-ATP binding. The structure also shows the characteristic "molecular brake" mechanism, where the JM domain interacts with the kinase domain to maintain an autoinhibited state [8].

### 2.4 Structural Basis of Exon 14 Skipping

The JM domain (residues 946-1000) is a flexible, intrinsically disordered region that physically interacts with the kinase domain. This interaction stabilizes the inactive conformation by:
1. Preventing ATP binding through steric hindrance.
2. Positioning Y1003 for c-Cbl binding, which leads to receptor ubiquitination and degradation.

Loss of the JM domain (via exon 14 skipping) removes this autoinhibitory constraint, resulting in constitutive kinase activation. Structural studies show that the truncated receptor has a more open ATP-binding pocket, increasing its affinity for ATP and small-molecule inhibitors [4, 6, 7].

### 2.5 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load MET (PDB: 2RFS)](/tools/protein-structure-viewer?source=direct&pdbId=2RFS)

The visualizer allows exploration of the MET kinase domain in complex with a selective inhibitor. Key structural features to examine include:
- The ATP-binding pocket and hinge region (residues 1155-1162).
- The activation loop (residues 1222-1245) and the DFG motif.
- The JM domain binding site on the kinase N-lobe.
- The allosteric pocket adjacent to the ATP site, which is targeted by type II inhibitors.

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 HGF Ligand and Receptor Activation

HGF is a pleiotropic cytokine secreted by mesenchymal cells. It is synthesized as a single-chain inactive precursor (pro-HGF) and is cleaved by serine proteases (e.g., HGF activator, matriptase, uPA) into an active two-chain form consisting of an α-chain (containing the N-terminal hairpin domain and four kringle domains) and a β-chain (containing a serine protease-like domain) [1, 2].

HGF binding to MET occurs through a two-step mechanism:
1. The HGF α-chain N-terminal domain binds to the MET Sema domain with high affinity.
2. The HGF β-chain interacts with the IPT domains, inducing a conformational change that promotes receptor dimerization.

Receptor dimerization brings two kinase domains into close proximity, enabling **trans-autophosphorylation** of Y1234 and Y1235 in the activation loop. This phosphorylation stabilizes the active kinase conformation and promotes phosphorylation of the C-terminal docking sites Y1349 and Y1356 [1, 7].

### 3.2 Downstream Signaling Cascades

The phosphorylated C-terminal tail (Y1349/Y1356) serves as a multisubstrate docking site for adaptor proteins containing Src homology 2 (SH2) domains or phosphotyrosine-binding (PTB) domains. The major downstream pathways include:

#### 3.2.1 RAS/MAPK Pathway
The adaptor protein **GRB2** binds directly to Y1356 and recruits the guanine nucleotide exchange factor **SOS**, which activates RAS. RAS-GTP triggers the RAF/MEK/ERK cascade, leading to cell proliferation and differentiation. This pathway is critical for the mitogenic effects of HGF [1, 4].

#### 3.2.2 PI3K/AKT Pathway
The p85 regulatory subunit of **PI3K** binds to the MET docking site via the adaptor **GAB1**. PI3K generates PIP3, which recruits **AKT** to the membrane, where it is phosphorylated and activated by PDK1 and mTORC2. AKT promotes cell survival, protein synthesis, and cell growth [1, 4].

#### 3.2.3 JAK/STAT Pathway
MET can directly phosphorylate **STAT3** at Y705, leading to STAT3 dimerization and nuclear translocation. STAT3 regulates genes involved in cell cycle progression, angiogenesis (VEGF), and immune evasion [9].

#### 3.2.4 PLCγ Pathway
**PLCγ** binds to the MET docking site and hydrolyzes PIP2 to generate IP3 and DAG. IP3 triggers calcium release from the ER, while DAG activates protein kinase C (PKC). PKC can phosphorylate S985 in the JM domain, providing negative feedback [1].

#### 3.2.5 β-Catenin/Wnt Pathway
MET activation leads to phosphorylation of β-catenin at Y654, promoting its dissociation from E-cadherin and nuclear translocation. Nuclear β-catenin activates Wnt target genes, contributing to epithelial-mesenchymal transition (EMT) [5].

### 3.3 Negative Regulation and Receptor Downregulation

MET signaling is tightly regulated by multiple mechanisms:

1. **c-Cbl-mediated ubiquitination**: Ligand-activated MET recruits the E3 ubiquitin ligase c-Cbl, which binds to phospho-Y1003. c-Cbl ubiquitinates the receptor, targeting it for clathrin-mediated endocytosis and lysosomal degradation [4, 5].
2. **Receptor tyrosine phosphatases (PTPs)**: DEP-1 (PTPRJ) directly dephosphorylates MET at the activation loop, terminating signaling [1].
3. **SOCS proteins**: Suppressor of cytokine signaling 1 (SOCS1) binds to MET and inhibits its kinase activity, providing another layer of negative regulation [2].
4. **Decorin**: The small leucine-rich proteoglycan decorin binds to MET and acts as a partial agonist, inducing receptor internalization and degradation [3].

### 3.4 Protein-Protein Interaction Network

The MET interactome is extensive, with over 100 confirmed binding partners (BioGRID). Key interactions include:

| **Interactor** | **Binding Region** | **Functional Consequence** |
|:---|:---|:---|
| HGF | Sema domain | Ligand-induced activation |
| GRB2 | Y1356 | RAS/MAPK activation |
| GAB1 | Y1349/Y1356 | PI3K/AKT activation |
| c-Cbl | Y1003 | Ubiquitination and degradation |
| STAT3 | Kinase domain | Direct phosphorylation |
| PLCγ | Y1349/Y1356 | Calcium signaling |
| SHP2 | Y1349 | RAS/MAPK amplification |
| DEP-1 | Kinase domain | Dephosphorylation |
| SOCS1 | Kinase domain | Kinase inhibition |
| PAX6 | Promoter (indirect) | Transcriptional regulation |

### 3.5 Mermaid Signaling Pathway Diagram

```mermaid
sequenceDiagram
    participant M as "Mesenchymal Cell"
    participant HGF as "HGF (pro-form)"
    participant HGFa as "Active HGF"
    participant MET as "MET Receptor"
    participant GRB2 as "GRB2"
    participant SOS as "SOS"
    participant RAS as "RAS"
    participant RAF as "RAF"
    participant MEK as "MEK"
    participant ERK as "ERK"
    participant PI3K as "PI3K"
    participant AKT as "AKT"
    participant STAT3 as "STAT3"
    participant cCBL as "c-Cbl"
    M->>HGF: Secretion
    HGF->>HGFa: Proteolytic cleavage (uPA, matriptase)
    HGFa->>MET: Binding to Sema domain
    MET->>MET: Dimerization & trans-autophosphorylation (Y1234/Y1235)
    MET->>MET: Phosphorylation of Y1349/Y1356
    MET->>GRB2: Direct binding
    GRB2->>SOS: Recruitment
    SOS->>RAS: GDP→GTP exchange
    RAS->>RAF: Activation
    RAF->>MEK: Phosphorylation
    MEK->>ERK: Phosphorylation
    ERK->>ERK: Nuclear translocation → Proliferation
    MET->>PI3K: Via GAB1
    PI3K->>AKT: PIP3 generation
    AKT->>AKT: Survival signals
    MET->>STAT3: Direct phosphorylation
    STAT3->>STAT3: Dimerization → Angiogenesis
    MET->>cCBL: Ubiquitination (Y1003)
    cCBL->>MET: Endocytosis & degradation
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 MET Exon 14 Skipping Mutations

Exon 14 skipping mutations are the most well-characterized oncogenic alterations in MET. These mutations occur in the splice donor or acceptor sites flanking exon 14, or within the exon itself, and result in the in-frame deletion of the JM domain [4, 6, 7].

**Mechanism**: The loss of the JM domain removes:
- Y1003 (c-Cbl binding site) → impaired receptor degradation
- S985 (PKC site) → loss of negative feedback
- The autoinhibitory interaction with the kinase domain → constitutive activation

**Prevalence**: Exon 14 skipping mutations are found in approximately **3-4% of NSCLC** cases, with higher prevalence in:
- Adenocarcinoma histology (up to 5%)
- Never-smokers
- Elderly patients
- Tumors with concurrent MET amplification (up to 20% of exon 14-mutant tumors)

**Mutation types**:
- Splice donor site mutations (e.g., c.3028+1G>A, c.3028+2T>C)
- Splice acceptor site mutations (e.g., c.3028-1G>A, c.3028-2A>G)
- Intronic mutations creating cryptic splice sites
- Exonic mutations affecting the exonic splicing enhancer (ESE) sequences

**Clinical significance**: Tumors with exon 14 skipping mutations are highly sensitive to MET inhibitors (capmatinib, tepotinib, crizotinib), with response rates of 40-68% in clinical trials [4, 6, 7].

### 4.2 MET Amplification

MET gene amplification is a well-established oncogenic driver and resistance mechanism:

- **Primary amplification**: Occurs in 1-5% of NSCLC, 10-20% of gastric cancer, and 5-10% of esophageal adenocarcinoma. High-level amplification (MET/CEP7 ratio > 2.0 or GCN ≥ 10) is associated with poor prognosis [4, 5, 6].
- **Acquired amplification**: Develops in 5-20% of EGFR-mutant NSCLC patients treated with EGFR TKIs (e.g., osimertinib). MET amplification activates the ERBB3/PI3K pathway, bypassing EGFR inhibition [1, 2, 7, 8, 9].
- **Amplification in other cancers**: MET amplification is also observed in glioblastoma, colorectal cancer, and biliary tract cancer [3, 4].

### 4.3 MET Kinase Domain Mutations

Activating point mutations in the kinase domain are less common but have been identified in:

- **Hereditary papillary renal cell carcinoma (HPRCC)**: Germline mutations in the kinase domain (e.g., M1149T, V1188L, D1228N, M1250T) predispose to HPRCC [5].
- **Childhood hepatocellular carcinoma**: Somatic mutations in the kinase domain (e.g., Y1230C, M1268I) have been reported [5].
- **NSCLC**: Acquired kinase domain mutations (e.g., D1228N, Y1230H) can emerge as resistance mechanisms to MET TKIs [6].

### 4.4 MET Overexpression Without Amplification

MET protein overexpression can occur through:
- Transcriptional upregulation (e.g., via PAX6, HIF-1α under hypoxia)
- Reduced degradation (e.g., loss of c-Cbl function)
- Autocrine/paracrine HGF stimulation

MET overexpression is associated with poor prognosis in multiple cancers, including head and neck squamous cell carcinoma, breast cancer, and mesothelioma [4, 6, 7].

### 4.5 MET Gene Fusions

MET gene fusions are rare but targetable alterations. The most common fusion partner is **HLA-DRB1**, resulting in an in-frame fusion that drives ligand-independent MET activation. These fusions have been reported in NSCLC and are sensitive to MET inhibitors (crizotinib, tepotinib) [1, 8, 9].

### 4.6 MET Promoter Variants and Neurodevelopmental Disorders

The **rs1858830 C allele** in the MET promoter is associated with:
- Increased risk for autism spectrum disorder (ASD) [1, 2, 3, 4]
- Reduced MET expression in the temporal cortex
- Altered cortical thickness in children and adolescents [2]
- Gene-environment interactions with air pollution exposure [1]

Other MET variants have been implicated in Rett syndrome and intellectual disability [2].

### 4.7 ClinVar Classification of Key Variants

| **Variant** | **Protein Change** | **ClinVar Classification** | **Associated Condition** |
|:---|:---|:---|:---|
| c.3028+1G>A | Exon 14 skipping | Pathogenic | NSCLC |
| c.3028+2T>C | Exon 14 skipping | Pathogenic | NSCLC |
| c.3028-1G>A | Exon 14 skipping | Pathogenic | NSCLC |
| c.3757T>C | M1253T | Pathogenic | HPRCC |
| c.3758A>G | M1253T | Pathogenic | HPRCC |
| c.3682A>G | M1228V | Pathogenic | HPRCC |
| rs1858830 (C allele) | Promoter variant | Risk factor | ASD |

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Interactions

MET signaling is exploited by several viruses to enhance their replication and spread:

- **Hepatitis B virus (HBV)**: HBV X protein (HBx) upregulates MET expression in hepatocytes, promoting liver cancer development. HBx activates the MET promoter through the transcription factor AP-1 [4].
- **Hepatitis C virus (HCV)**: HCV core protein enhances HGF/MET signaling, contributing to hepatocellular carcinoma progression.
- **Epstein-Barr virus (EBV)**: EBV latent membrane protein 1 (LMP1) induces MET expression in nasopharyngeal carcinoma cells, promoting invasion and metastasis.

### 5.2 Bacterial Interactions

- **Helicobacter pylori**: H. pylori infection upregulates MET expression in gastric epithelial cells. The bacterial virulence factor CagA interacts with MET and enhances its signaling, contributing to gastric carcinogenesis [4].

### 5.3 Antiviral Innate Immunity

Recent research has revealed a kinase-independent role for MET in antiviral immunity. MET is essential for the induction of type I interferons (IFN) in response to viral infection. Mechanistically, MET interacts with the mitochondrial antiviral signaling protein (MAVS) and is required for the activation of IRF3 and NF-κB. This function is independent of MET's kinase activity, as kinase-dead MET mutants retain antiviral activity [3].

### 5.4 Parasitic Infections

- **[Toxoplasma gondii](/knowledge/parasites/protozoa/toxoplasma-gondii-lifecycle-neurological-infection)**: Infection with T. gondii has been shown to modulate MET expression in the brain, potentially contributing to neurodevelopmental abnormalities [4].

---

## 6. [Pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), Drug Targets & Small-Molecule Inhibitors

### 6.1 FDA-Approved MET Inhibitors

| **Drug** | **Class** | **Target** | **Approved Indications** | **Key Clinical Data** |
|:---|:---|:---|:---|:---|
| **Capmatinib (Tabrecta)** | Type Ib ATP-competitive | MET | NSCLC with exon 14 skipping | GEOMETRY mono-1 trial: ORR 68% in treatment-naïve patients; 41% in previously treated [7] |
| **Tepotinib (Tepmetko)** | Type Ib ATP-competitive | MET | NSCLC with exon 14 skipping | VISION trial: ORR 46% overall; 54% in treatment-naïve [7, 9] |
| **Crizotinib (Xalkori)** | Type Ia ATP-competitive | ALK, ROS1, MET | NSCLC with ALK/ROS1 alterations; off-label for MET | PROFILE trials; active against MET exon 14 and amplification [4, 8] |

### 6.2 Investigational MET Inhibitors

| **Drug** | **Class** | **Development Stage** | **Notes** |
|:---|:---|:---|:---|
| **Savolitinib** | Type Ib ATP-competitive | Phase III | Active in MET exon 14 NSCLC and MET-amplified gastric cancer |
| **AMG-337** | Type Ib ATP-competitive | Phase II | Discontinued due to toxicity |
| **SGX523** | Type Ib ATP-competitive | Phase I | Discontinued due to renal toxicity; highly selective [8] |
| **SAR125844** | Type II ATP-competitive | Phase I | Active in MET-amplified tumors [5] |
| **Merestinib** | Type II ATP-competitive | Phase II | Multikinase inhibitor with MET activity |
| **Cabozantinib** | Type II ATP-competitive | Approved (other indications) | Multikinase inhibitor (MET, VEGFR2, AXL, RET) |

### 6.3 Monoclonal Antibodies

| **Antibody** | **Type** | **Mechanism** | **Development Stage** |
|:---|:---|:---|:---|
| **Onartuzumab** | Monovalent (one-armed) anti-MET | Blocks HGF binding | Phase III (failed in MET-positive NSCLC) |
| **Emibetuzumab** | Bivalent anti-MET | Blocks HGF binding; induces receptor internalization | Phase II |
| **LY2875358** | Bivalent anti-MET | Blocks HGF binding; induces receptor internalization | Phase II |
| **ABT-700** | Bivalent anti-MET | Blocks HGF binding | Preclinical |

### 6.4 Resistance Mechanisms to MET Inhibitors

Resistance to MET-targeted therapies can arise through:

1. **On-target resistance**: Secondary mutations in the MET kinase domain (e.g., D1228N, Y1230H) that prevent drug binding [6].
2. **Off-target resistance**: Activation of bypass signaling pathways, including:
   - KRAS amplification [6]
   - EGFR activation
   - AXL upregulation [7]
   - FGFR signaling
3. **Phenotypic resistance**: Epithelial-mesenchymal transition (EMT) and tumor plasticity [8, 9].

### 6.5 MET as a Resistance Mechanism to EGFR TKIs

MET amplification is a major mechanism of acquired resistance to EGFR TKIs in NSCLC:

- **Prevalence**: 5-20% of osimertinib-resistant tumors harbor MET amplification [2, 7, 9].
- **Mechanism**: MET activates the ERBB3/PI3K/AKT pathway, bypassing EGFR inhibition [1, 8].
- **Therapeutic strategy**: Combination of EGFR TKI (osimertinib) with MET TKI (savolitinib, capmatinib, tepotinib) is under investigation in clinical trials [2, 9].

### 6.6 Pharmacogenomic Considerations

- **[CYP3A4](/knowledge/bioinformatics/genes/medical-genetics/cyp3a4-gene-structure-function-pathway) metabolism**: Capmatinib and tepotinib are metabolized by CYP3A4. Strong CYP3A4 inhibitors (e.g., ketoconazole) increase drug exposure, while inducers (e.g., rifampin) decrease exposure.
- **Drug-drug interactions**: Crizotinib inhibits CYP3A4 and should be used with caution with other CYP3A4 substrates.
- **Renal function**: Tepotinib requires dose adjustment in patients with severe renal impairment.

---

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession/ID** | **URL** |
|:---|:---|:---|
| **NCBI Gene** | 4233 | https://www.ncbi.nlm.nih.gov/gene/4233 |
| **Ensembl** | ENSG00000105976 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105976 |
| **UniProt** | P08581 | https://www.uniprot.org/uniprotkb/P08581 |
| **RCSB PDB** | 2RFS | https://www.rcsb.org/structure/2RFS |
| **OMIM** | 164860 | https://www.omim.org/entry/164860 |
| **ClinVar** | Gene: MET | https://www.ncbi.nlm.nih.gov/clinvar/?term=MET%5Bgene%5D |
| **COSMIC** | MET | https://cancer.sanger.ac.uk/cosmic |
| **STRING** | P08581 | https://string-db.org/network/P08581 |
| **BioGRID** | 112590 | https://thebiogrid.org/112590 |
| **PharmGKB** | PA30889 | https://www.pharmgkb.org/gene/PA30889 |
| **GTEx** | MET | https://gtexportal.org/home/gene/MET |
| **Human Protein Atlas** | ENSG00000105976 | https://www.proteinatlas.org/ENSG00000105976-MET |

### Gene Ontology (GO) Terms

| **Category** | **GO Term** | **Accession** |
|:---|:---|:---|
| **Molecular Function** | Transmembrane receptor protein tyrosine kinase activity | GO:0004714 |
| **Molecular Function** | Hepatocyte growth factor receptor activity | GO:0005006 |
| **Molecular Function** | Protein tyrosine kinase activity | GO:0004713 |
| **Molecular Function** | ATP binding | GO:0005524 |
| **Biological Process** | Cell proliferation | GO:0008283 |
| **Biological Process** | Cell migration | GO:0016477 |
| **Biological Process** | Epithelial to mesenchymal transition | GO:0001837 |
| **Biological Process** | Nervous system development | GO:0007399 |
| **Biological Process** | Wound healing | GO:0042060 |
| **Cellular Component** | Plasma membrane | GO:0005886 |
| **Cellular Component** | Receptor complex | GO:0043235 |
| **Cellular Component** | Cytoplasm | GO:0005737 |

---

## Related Clinical & Scientific Guides

* [PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition](/knowledge/bioinformatics/genes/cancer-genomics/pik3ca-gene-structure-function-pathway)
* [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway)
* [PDGFB Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/pdgfb-gene-structure-function-pathway)

## References

[1] Al-Ghabkari, A., Huang, B., & Park, M. (2024). Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions. *Cells*. https://www.semanticscholar.org/paper/6e5b8f4a41d86c193bcd9c24e7d8628283d025e8

[2] Zhang, Y., Xia, M., Jin, K., Wang, S., Wei, H., Fan, C., Wu, Y., Li, X., Li, X., Li, G., Zeng, Z., & Xiong, W. (2018). Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. *Molecular Cancer*. https://www.semanticscholar.org/paper/1ea3d88bffae61095cb07533687bccbca40cecea

[3] Volk, H., Kerin, T., Lurmann, F., Hertz-Picciotto, I., McConnell, R., & Campbell, D. (2014). Interaction of the MET Receptor Tyrosine Kinase Gene and Air Pollution Exposure in Autism Spectrum Disorder. *Epidemiology*. https://www.semanticscholar.org/paper/24986971b5e4467046db68ee08e8d62d9fe8d26a

[4] Xia, B., Wei, J., Ma, X., Nehme, A., Liong, K., Cui, Y., Chen, C., Gallitano, A., Ferguson, D., & Qiu, S. (2021). Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice. *Neurobiology of Learning and Memory*. https://www.semanticscholar.org/paper/519f37a57c54df15ca4c60def7114925f7490335

[5] Yao, H., Tong, X., & Wang, M. (2021). Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase. *Therapeutic Advances in Medical Oncology*. https://www.semanticscholar.org/paper/675c86609b0ea75a5a562991a7dcce04646e45de

[6] Chen, K., Ma, X., Nehme, A., Wei, J., Cui, Y., Cui, Y., Yao, D., Wu, J., Anderson, T., Ferguson, D., Levitt, P., & Qiu, S. (2020). Time-delimited signaling of MET receptor tyrosine kinase regulates cortical circuit development and critical period plasticity. *Molecular Psychiatry*. https://www.semanticscholar.org/paper/756804d0dd906ca7560d6a5513704c599fe110ad

[7] Judson, M. C., Bergman, M., Campbell, D. B., Eagleson, K., & Levitt, P. (2009). Dynamic gene and protein expression patterns of the autism-associated Met receptor tyrosine kinase in the developing mouse forebrain. *The Journal of Comparative Neurology*. https://www.semanticscholar.org/paper/62ad620cb5a0ba76b802c31799b261e09adb020b

[8] Plummer, J. T., Evgrafov, O. V., Bergman, M., Friez, M., Haiman, C., Levitt, P., & Aldinger, K. A. (2013). Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. *Translational Psychiatry*. https://www.semanticscholar.org/paper/0a5c41497e2e92c25cf8d9e34683ca5251d4fbd8

[9] Peng, Y., Lu, Z., Li, G., Piechowicz, M., Anderson, M. R., Uddin, Y., Wu, J., & Qiu, S. (2016). The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain. *Molecular Psychiatry*. https://www.semanticscholar.org/paper/1daf99c00b431