MET Proto-Oncogene, Receptor Tyrosine Kinase
The primary translation product of the c-MET protein is a 170 kDa single-chain precursor (pro-c-MET), which is proteolytically cleaved by furin endopeptidase in the Golgi apparatus at the R307-S308 site to generate the mature heterodimer. This mature c-MET heterodimer consists of two subunits covalently linked by disulfide bonds: an extracellular α-chain (32 kDa) and a β-chain (120 kDa) that harbors both the transmembrane and intracellular domains.
The extracellular domain (ECD) encompasses the following core structural modules: (1) the Semaphorin (SEMA) domain – spanning the N-terminal regions of both the α- and β-chains and comprising approximately 500 amino acids with multiple conserved cysteine residues – which folds into a beta-propeller configuration and serves as the critical region for direct ligand (HGF) binding; (2) the Plexin-Semaphorin-Integrin (PSI) hinge domain, approximately 50 amino acids in length, which connects the SEMA and IPT domains and contains conserved disulfide bonds essential for sustaining the overall conformational stability of the ECD; and (3) four tandem Immunoglobulin-Plexin-Transcription factor (IPT 1–4) repeat domains, each consisting of about 90 amino acids, which cooperatively facilitate HGF engagement and receptor dimerization-mediated activation.
The transmembrane domain (TMD), located in the middle portion of the β-chain, consists of a single hydrophobic α-helix that mediates receptor anchoring within the lipid bilayer of the plasma membrane and facilitates signal transduction across the membrane. The intracellular domain (ICD) exhibits a complex architecture, comprising, in sequential order: (1) the juxtamembrane (JM) domain – upon phosphorylation at Y1003, it recruits the E3 ubiquitin ligase CBL, which negatively regulates c‑MET endocytic degradation, thereby serving as a critical node for receptor signal termination; (2) the bilobed tyrosine kinase domain – trans‑autophosphorylation at Y1234 and Y1235 is a prerequisite for full receptor activation, with Y1230 also participating in the regulation of the kinase activation loop; and (3) the C‑terminal multifunctional docking site – following phosphorylation at Y1349 and Y1356, this site recruits SH2 domain‑containing adaptor proteins (e.g., GRB2, GAB1, the PI3K regulatory subunit, SHIP2, and SRC), which in turn activate multiple downstream signaling cascades, including the PI3K/AKT, Ras/MAPK, JAK/STAT, and Wnt/β‑catenin pathways. In addition, c‑MET possesses multiple N‑glycosylation sites, particularly within the SEMA and IPT domains; glycosylation plays a pivotal regulatory role in receptor folding, membrane trafficking, and ligand‑binding affinity.
The c‑MET protein is highly conserved among mammals. Human MET (UniProt P08581, 1390 aa) and murine Met (UniProt P16056, 1379 aa) share approximately 90% amino acid sequence homology over the entire protein, with the intracellular kinase domain being the most conserved region (>95% homology). The SEMA domain and IPT repeats exhibit about 85–90% homology, whereas the key phosphorylatable residues within the C‑terminal docking site (Tyr1349 and Tyr1356 in human) are strictly conserved in the murine ortholog.
In human normal tissues, c‑MET expression is most abundant in the liver (RPKM 253.1) and kidney (RPKM 289.7), with appreciable but variable expression also detected in the lung, gastric mucosa, colorectal epithelium, thyroid, pancreas, skeletal muscle precursor cells (satellite cells), neurons, and endothelial cells. During embryonic development, c‑MET is broadly expressed and participates in morphogenesis of multiple organs; in adulthood, its expression is tightly regulated and becomes predominantly confined to epithelial cells and stem/progenitor cell populations.
The sole known ligand of c‑MET is hepatocyte growth factor (HGF), also termed scatter factor (SF), which is secreted by stromal fibroblasts and acts in a paracrine manner. Upon binding to the extracellular SEMA and IPT domains of MET, HGF induces receptor homodimerization, which is followed by trans‑autophosphorylation at Tyr1234 and Tyr1235 within the intracellular kinase domain, thereby achieving full receptor activation. Subsequently, phosphorylation of the C‑terminal docking tyrosines Tyr1349 and Tyr1356 recruits SH2‑domain‑containing adaptor proteins, including GRB2, GAB1, PI3K, and SRC, leading to the activation of the following major signaling cascades: the PI3K/AKT pathway (promoting cell survival and anti‑apoptosis), the Ras/MAPK pathway (driving proliferation and cell‑cycle progression), the JAK/STAT pathway (mediating transcriptional regulation), the Wnt/β‑catenin pathway (involved in stem‑cell maintenance and tissue regeneration), and the SRC family kinase pathway (regulating cell migration and invasion).
Under physiological conditions, the HGF/c‑MET axis serves as a central signaling hub that governs epithelial cell proliferation, morphogenesis, angiogenesis, and tissue repair/regeneration, playing indispensable roles in liver regeneration, renal repair, muscle regeneration, and nervous system development. Signal termination is accomplished through multiple mechanisms, including: recruitment of the E3 ubiquitin ligase CBL upon Y1003 phosphorylation in the juxtamembrane domain, which mediates K48‑linked polyubiquitination of c‑MET and subsequent proteasomal degradation; endocytosis of the receptor–ligand complex followed by lysosomal degradation; and inhibition exerted by negative feedback regulators such as MIG6 (ERRFI1).
In various solid tumors, c‑MET undergoes aberrant activation through multiple mechanisms, including gene amplification, exon 14 skipping (METex14), gene fusions (MET fusions), protein overexpression, and point mutations (e.g., kinase domain‑activating mutations associated with hereditary papillary renal carcinoma [HPRC]), thereby serving as either a critical oncogenic driver or a resistance bypass pathway.
In non‑small cell lung cancer (NSCLC), the incidence of METex14 skipping mutations ranges from 3% to 4%, primary MET amplification is observed in approximately 1%–5% of cases, while secondary MET amplification—emerging as an acquired resistance mechanism to EGFR‑TKIs—occurs in about 5%–20% of cases. c‑MET protein overexpression (IHC 2+/3+) is detected in roughly 25%–65% of NSCLCs; among these, high‑level expression (IHC 3+, defined as ≥50% tumor cells) meeting the approval criteria for telisotuzumab vedotin accounts for approximately 14.4% of non‑squamous NSCLC. In gastric cancer/gastroesophageal junction (GEJ) cancer, MET amplification is found in about 4%–10% of cases, while overexpression is present in roughly 50%. In renal cell carcinoma (particularly type 1 papillary renal cell carcinoma), germline MET‑activating mutations are seen in all cases of hereditary papillary renal carcinoma (HPRC), and MET mutations are identified in approximately 13%–15% of sporadic type 1 tumors. In colorectal cancer (CRC), MET amplification—most frequently as a secondary resistance mechanism to EGFR monoclonal antibody therapy—occurs in about 5%–12% of cases; in hepatocellular carcinoma (HCC), c‑MET overexpression is reported in approximately 40%–70% of cases.
JNJ‑61186372 (Amivantamab) is a bispecific antibody targeting both the epidermal growth factor receptor (EGFR) and the mesenchymal‑epithelial transition factor (MET) pathways, engineered using Genmab's DuoBody platform. This antibody is primarily directed against EGFR exon 20 insertion (Exon20ins) mutations and c‑MET amplification drivers, and is also applicable to resistance mechanisms associated with ALK rearrangements, with the aim of addressing tyrosine kinase inhibitor (TKI) resistance in non‑small cell lung cancer (NSCLC). Amivantamab incorporates a low‑fucosylation design (<10%), which enhances Fc‑mediated effector functions, including antibody‑dependent cell‑mediated cytotoxicity (ADCC) and monocyte/macrophage‑mediated trogocytosis, thereby promoting receptor downregulation and augmenting antitumor activity. Its dual‑targeting mechanism, through synergistic inhibition of EGFR and MET signaling combined with immune‑mediated effects, offers a novel therapeutic strategy to overcome TKI resistance. The authors postulate that Amivantamab exhibits high affinity for c‑MET (Kd = 40 pmol/L) while displaying relatively lower affinity for EGFR (Kd = 1.4 nmol/L); its Fc region, modified by low fucosylation, efficiently binds FcγRIIIa. These three features act synergistically to confer upon Amivantamab superior target selectivity, enhanced efficacy, and reduced toxicity relative to cetuximab.
In NSCLC models driven by EGFR Exon20ins mutations, including Ba/F3 cells and patient‑derived cell lines, Amivantamab effectively inhibits cell proliferation through a mechanism involving downregulation of EGFR and MET receptor expression and the induction of an immune‑oriented antitumor response characterized by increased IFNγ secretion. In the absence of immune cells, the antiproliferative effect and receptor downregulation mediated by this antibody are relatively limited; however, upon supplementation with human immune cells (e.g., monocytes/macrophages), Amivantamab enhances EGFR and MET downregulation via a trogocytic mechanism, thereby inducing a dose‑dependent cancer cell killing response. In ALK‑rearranged NSCLC cell lines (H3122, ABC‑19), Amivantamab augments the antitumor activity of alectinib through EGFR inhibition; nevertheless, certain cell lines (e.g., ABC‑11) exhibit resistance to EGFR/MET pathway inhibition unless immune cell support is provided.
In EGFR Exon20ins‑driven NSCLC xenograft models, Amivantamab demonstrated superior antitumor activity compared with cetuximab and the small‑molecule inhibitor poziotinib, inducing marked tumor regression. In the HCC827‑HGF model, its efficacy also surpassed that of conventional EGFR or MET inhibitors, suggesting a broader spectrum of activity. The in vivo activity of Amivantamab is primarily dependent on Fc‑mediated mechanisms; in contrast, Fc‑silenced variants or single‑targeting antibodies (against either EGFR or MET) exhibited substantially diminished tumor growth inhibition. In vivo, Amivantamab effectively downregulated EGFR and MET receptor expression, and its antitumor effects were dependent on macrophage‑mediated phagocytic activity. In ALK‑rearranged NSCLC models, the antibody significantly restored sensitivity to alectinib in the presence of immune cells, highlighting its dual antitumor mechanism that synergistically combines signaling pathway inhibition with immune effector functions.
The c‑MET/HGF inhibitor market has entered a phase of rapid expansion. According to statistics from Beijing Ze Consulting (2025), the global c‑MET and HGF inhibitor market reached approximately RMB 27.713 billion (around USD 3.8 billion) in 2024, with the Chinese market accounting for about RMB 8.677 billion. Global Market Monitor projects a compound annual growth rate (CAGR) of approximately 31.04% from 2024 to 2029. Additionally, data from Verified Market Reports indicate that the global market, valued at approximately USD 2.5 billion in 2022, is expected to exceed USD 5.0 billion by 2030. This growth is driven by the expanding adoption of precision medicine biomarker testing (e.g., METex14), regulatory approvals of novel molecular formats (bispecific antibodies and ADCs), and the extension of indications to gastric cancer, colorectal cancer, renal cell carcinoma, and other tumor types.
Representative product performance and forecasts: Capmatinib (TABRECTA®, Novartis) and tepotinib (TEPMETKO®, Merck KGaA) currently generate annual sales in the range of USD 0.5–1.0 billion each. Although the global METex14‑positive NSCLC patient population is estimated at approximately 40,000 cases (based on an incidence of 3%–4% among the approximately 2.4 million annual new NSCLC cases worldwide), the addressable patient population remains relatively limited. In contrast, Telisotuzumab vedotin (EMRELIS®), targeting c‑MET‑overexpressing (approximately 14.4%) non‑squamous NSCLC, substantially expands the potential market, with an estimated annual global incidence exceeding 200,000 new cases and projected peak sales of USD 1.5–2.5 billion (post‑2030). Amivantamab (RYBREVANT®, Johnson & Johnson) achieved annual sales exceeding USD 0.5 billion in 2024; supported by the combination with lazertinib (the MARIPOSA regimen) for first‑line treatment of EGFR‑mutant NSCLC, it is anticipated to reach peak sales of USD 2.0–3.0 billion within the next five years. Investment and licensing activity in the c‑MET antibody space (including bispecific antibodies and ADCs) has remained robust, with multiple billion‑dollar business development transactions between 2023 and 2025—such as AbbVie's ABBV‑400 series and the savolitinib co‑development collaboration between AstraZeneca and HUTCHMED—reinforcing the industry's strong commercial confidence in this target.
Key drivers of market growth include: (1) standardization of MET biomarker testing (integrating NGS, FISH, and IHC modalities) to accelerate precise patient screening; (2) the substantial patient population with acquired resistance to EGFR‑TKIs (with more than 600,000 annual new cases of EGFR‑mutant NSCLC globally), creating an urgent demand for combination strategies with c‑MET‑targeted agents; (3) technological advancements in ADC platforms (optimized linkers/payloads) and maturation of bispecific antibody platforms, further expanding the eligibility criteria for c‑MET‑directed therapies; and (4) the domestic approval of savolitinib in China and the ongoing development of local ADC pipelines, positioning the Asia‑Pacific market as a key growth region.
The competitive landscape of c‑MET‑targeted therapies is characterized by a "multi‑modality, multi‑player" paradigm, encompassing diverse technological platforms including TKIs, monoclonal antibodies, bispecific antibodies (BsAbs), antibody–drug conjugates (ADCs), and combination strategies. These therapeutic agents are highly differentiated in terms of biomarker selection, mechanisms of action, and indicated patient populations.
The TKI segment has matured, with three approved products competing for the METex14+ market: (1) capmatinib (TABRECTA®, Novartis; type Ib TKI) – demonstrating an objective response rate (ORR) of approximately 68% in treatment‑naïve METex14‑positive patients, received FDA approval in 2020 and EMA approval in 2021, and maintains a dominant global position; (2) tepotinib (TEPMETKO®, Merck KGaA; type Ib TKI) – supported by data from the VISION study, with an ORR of approximately 55% in the liquid‑biopsy‑selected population; and (3) savolitinib (ORPATHYS®, AstraZeneca/HUTCHMED; type Ib TKI) – approved in China in 2021, with mature data from the CONFIRM study published in 2024, currently leading the Chinese market. Next‑generation TKIs (e.g., vabametkib, gumarontinib among type Ib agents, and type IIb agents such as cabozantinib) are being developed to address resistance to first‑generation Ia/Ib TKIs.
In the bispecific antibody arena, the most representative agent is Amivantamab (RYBREVANT®, JRD/Janssen; EGFR/MET bispecific antibody) – granted FDA approval in 2021 for EGFR exon 20 insertion‑mutant NSCLC, with multiple additional indications approved since 2023, and a third indication in China (EGFR 19del/L858R in combination with lazertinib, based on the MARIPOSA study) approved in 2025. Its distinctive mechanism of action integrates three modalities: receptor degradation (via ectodomain targeting), ADCC/ADCP (Fc effector functions), and signaling blockade. Several other EGFR/c‑MET bispecific antibodies, including MCLA‑129 (Merus/AbbVie) and EMB‑01 (EpimAb), are currently in Phase I/II clinical development.
In the ADC sector, Telisotuzumab vedotin (EMRELIS®, AbbVie) became the first c‑MET‑targeted ADC to receive approval in May 2025, establishing a novel therapeutic niche for high‑expressing non‑squamous NSCLC. ABBV‑400 (Telisotuzumab adizutecan, AbbVie; Topo‑I inhibitor payload) has entered Phase I trials as a next‑generation c‑MET ADC. REGN5093‑M114 (Regeneron; MET×MET bispecific ADC with a DM1 payload) is under investigation in Phase 1/2 studies for MET‑amplified/overexpressing NSCLC, featuring a unique bivalent MET‑binding design. In the domestic Chinese landscape, multiple local companies (e.g., Rongchang Biopharma, Zhixiang Jintai, and Vlead Biopharma) have advanced c‑MET ADCs or bispecific antibodies into clinical stages, with intensifying competition. Key differentiation parameters include: biomarker cutoff thresholds (amplification vs. overexpression vs. mutation), Fc effector function engineering (ADCC/ADCP capacity), ADC payload selection (MMAE vs. DXd vs. DM1), and dual‑target combinations (EGFR/MET vs. MET/MET vs. single‑target c‑MET).
c‑Met is a receptor tyrosine kinase whose extracellular domain contains multiple pharmacologically accessible epitopes, including the SEMA, IPT, and PSI domains, enabling HGF binding and activation of downstream signaling pathways. c‑Met is overexpressed or amplified in a broad range of tumors, including non‑small cell lung cancer (NSCLC), gastric cancer, colorectal cancer, breast cancer, pancreatic cancer, and glioblastoma. Notably, METex14 mutations, which occur in approximately 3%–4% of NSCLC cases, constitute an independent oncogenic driver. Additional clinically relevant scenarios include MET amplification in the context of EGFR‑TKI resistance (observed in about 5%–20% of cases) and c‑Met protein overexpression in approximately 14% of non‑squamous NSCLC patients. Given its limited expression in normal tissues, c‑Met represents a selective target for antibody‑based therapeutics.
Mechanistically, c‑Met‑targeting antibodies exert their effects through multiple pathways: (i) competitive blockade of HGF binding to inhibit receptor activation; (ii) induction of receptor internalization and degradation, thereby attenuating signal transduction; (iii) Fc‑mediated antibody‑dependent cell‑mediated cytotoxicity (ADCC) and antibody‑dependent cellular phagocytosis (ADCP) to enhance immune effector functions; and (iv) in the case of antibody–drug conjugates (ADCs), selective delivery of cytotoxic payloads to c‑Met‑overexpressing tumor cells. Representative molecules include Telisotuzumab vedotin (a c‑Met ADC with an MMAE payload), MYTX‑011 (a pH‑dependent ADC), MCLA‑129 (an EGFR/c‑Met bispecific antibody), and Amivantamab (an EGFR/MET bispecific antibody), all of which have demonstrated clinical efficacy across distinct mechanistic contexts. Clinical validation has shown that Telisotuzumab vedotin achieves an objective response rate (ORR) of approximately 35% in patients with high c‑Met‑expressing NSCLC; MYTX‑011 has reported an ORR of approximately 38% across a broad range of expression levels; and MCLA‑129 has yielded ORRs of 40%–60% in METex14‑mutant cohorts, collectively underscoring the clinical value of c‑Met‑directed antibody therapies.
In terms of molecular format, c‑Met antibody therapeutics have evolved from monoclonal antibodies to bispecific antibodies (EGFR/c‑Met and MET×MET), ADCs (with MMAE or Topo‑I inhibitor payloads), nanobody‑based platforms, and even exploratory modalities such as CAR‑T cells. Strategically, c‑Met is a highly druggable target with demonstrated technical maturity, and the marketed products Telisotuzumab vedotin and Amivantamab have already established a clinical foundation. The market is expanding rapidly, with global sales estimated at approximately USD 3.8 billion in 2024 and projected to exceed USD 5.0 billion by 2030. Combined with active pipeline development and high‑value licensing deals (e.g., collaborations involving Roche, Hansoh, and Radiance), the c‑Met antibody therapeutic landscape represents a key direction in precision oncology for solid tumors, with substantial potential for continued expansion and commercial success.