c-MET: A Key Target in Cancer Therapy

The hepatocyte growth factor/c-MET signaling axis plays a critical role in early embryonic development, wound healing, and organ regeneration. However, pathological activation of c-MET can promote tumor growth and metastasis, making it an important therapeutic target in cancer treatment^[1][2].

Structure of c-MET

c-MET is a receptor tyrosine kinase (RTK) encoded by the MET gene located on chromosome 7q31. The c-MET receptor is initially synthesized as a single-chain precursor protein (pro-c-MET). Following cleavage by furin (between residues R307 and S308), pro-c-MET is converted into a mature heterodimer (mature c-MET) composed of an extracellular α-chain and a single-pass transmembrane β-chain linked by disulfide bonds^[2][3]. The extracellular region contains one N-terminal SEMA domain, one PSI domain, and four IPT domains (IPT1–4). The intracellular region comprises the juxtamembrane (JM) domain, the tyrosine kinase (TK) domain, and a C-terminal multifunctional docking site (MFDS), which together regulate kinase activity and downstream signal transduction^[1].

Conversion of pro-c-MET to mature c-MET structures^[3]

Similar to c-MET, hepatocyte growth factor (HGF) is also synthesized as an inactive precursor (pro-HGF). After activation by extracellular serine proteases, it forms a heterodimer consisting of disulfide-linked α and β chains. HGF is mainly secreted by stromal cells and activates c-MET on neighboring epithelial cells via paracrine signaling. Structurally, HGF contains an N-terminal hairpin loop, four kringle domains (K1–K4) in the α-chain, and a C-terminal serine protease homology (SPH) domain in the β-chain.

HGF binds to c-MET via two distinct sites:

• A low-affinity binding site within the SPH domain, which interacts with the SEMA domain of c-MET

• A high-affinity binding site located at the N-terminus and K1 domain, which interacts with the IPT3–IPT4 region of c-MET

Schematic representation of c-MET and HGF structures and binding sites^[1]

The c-MET Signaling Pathway

c-MET is primarily expressed on the surface of epithelial cells, where it plays a fundamental role in embryogenesis, wound healing, and organ regeneration. c-MET initiates signaling cascades upon binding of HGF, which induces c-MET homodimerization and trans-phosphorylation of the activation loop. Subsequent phosphorylation of C-terminal tyrosines (Y1349 & Y1356) creates a multifunctional docking site that recruits signal transducing proteins including GAB1 and GRB2. This engages the downstream Ras-MAPK/ERK pathway and the PI3K-Akt axis driving proliferation, cell migration, and cell survival^[4].

Under normal physiological conditions, the HGF/c-MET signaling pathway is tightly regulated by negative feedback mechanisms. Upon HGF-induced activation of c-MET, phosphorylation at Y1003 recruits the E3 ubiquitin ligase CBL, leading to ubiquitination of c-MET. The receptor is then trafficked to clathrin-coated vesicles (CCVs) and internalized via endocytosis. Early endosomes subsequently fuse with late endosomes to form multivesicular bodies (MVBs), which are transported to lysosomes where c-MET undergoes proteolytic degradation. Additionally, proteolytic cleavage represents another regulatory mechanism. ADAM proteases mediate shedding of the extracellular domain of c-MET, generating a soluble N-terminal fragment that acts as a decoy to antagonize c-MET dimerization and signaling^[5].

In metastatic or drug-resistant cancers, the regulatory control of c-MET is often compromised, resulting in oncogenic activation through either HGF-dependent or HGF-independent mechanisms. HGF-dependent activation involves receptors that fail to degrade properly or are hyper-stimulated by autocrine HGF production. In contrast, HGF-independent activation occurs when the receptor bypasses the need for its ligand entirely through MET gene amplification or constitutive mutations that force the kinase into an active configuration^[6]. Both pathways converge on the phosphorylation of cytoplasmic signaling motifs, driving hypersignaling and fueling tumor growth and invasive metastasis.

c-MET signaling pathway^[1]

Beyond the classical HGF-dependent activation pathway, c-MET can also be activated through non-canonical pathways via interactions with other receptors such as integrin α6β4, EGFR, CD44v6, Plexin B, HER2, HER3, and AXL. These pathways are closely associated with c-MET amplification, tumor drug resistance, and malignant phenotypes^[7].

c-MET is routinely overexpressed at baseline across various non-small cell lung cancer (NSCLC) subtypes, including those with EGFR mutations. Notably, 5-22% of tumors that develop resistance to EGFR tyrosine kinase inhibitors (TKIs) exhibit c-MET amplification, demonstrating the tumor’s capacity to exploit multiple signaling mechanisms to bypass therapeutic inhibition^[8].

Developments in c-MET-Targeted Therapeutics

Therapeutic strategies targeting c-MET include antibody–drug conjugates (ADCs), monoclonal antibodies, and bispecific antibodies. AbbVie’s “twin-star pipeline” includes Telisotuzumab vedotin (ABBV-399) and Telisotuzumab adizutecan (ABBV-400), both based on the ABT-700 antibody and conjugated with MMAE (a microtubule inhibitor) and adizutecan (a topoisomerase I inhibitor), respectively.

ABBV-399 is the first c-MET ADC approved by the FDA. It is indicated for patients with locally advanced or metastatic non-squamous NSCLC with high c-MET overexpression (≥50% of tumor cells showing 3+ strong staining by IHC). Its approval was based on positive results from the LUMINOSITY trial (NCT03539536). Among 84 patients with EGFR wild-type, high c-MET-expressing non-squamous NSCLC, the objective response rate (ORR) was 35% (95% CI: 24–46), and the median duration of response (mDOR) was 7.2 months (95% CI: 4.2–12)^[9]. ABBV-399 targets the SEMA domain of c-MET, blocking HGF binding and inducing receptor internalization, degradation, or cytotoxic effects^[10].

Schematic structure of Telisotuzumab vedotin (ABBV-399)^[3]

In the bispecific antibody field, Johnson & Johnson’s Amivantamab-vmjw has been approved for clinical use. This antibody simultaneously targets the extracellular domains of EGFR and c-MET and shows activity in NSCLC patients harboring EGFR exon 20 insertion mutations (ex20ins) as well as those who have developed resistance to third-generation EGFR TKIs^[11].

Mechanism of action of Amivantamab-VMJM^[8]

Selected c-MET-Targeted Drugs

KACTUS High-Quality c-MET Proteins

As the landscape of c-MET-targeted drug development evolves, the requirement for native-conformation proteins has only grown. For research programs addressing primary MET alterations or investigating c-MET-driven EGFR-TKI resistance, the success of lead discovery depends heavily on the structural integrity of the target antigen. KACTUS offers a comprehensive catalog of high-purity c-MET and specific domain proteins (including SEMA, IPT, and extracellular domains) across multiple species and with diverse tag formats. All products undergo stringent quality control and are suitable for diverse application scenarios, strongly supporting the development of c-MET-targeted therapeutics.

Product Performance Data

The bioactivity of HGF and c-MET (HGF R) is thoroughly evaluated using reciprocal validation. High-affinity binding of both recombinant HGF and c-MET are ensured through rigorous ELISA, SPR, and BLI testing.

Immobilized Human HGF R, His Tag at 1 μg/mL (100 μL/well). Dose-response curve for Human HGF, hFc Tag with an EC₅₀ of 10.1 ng/mL determined by ELISA (QC test).

 Immobilized Human HGF R, His Tag at 0.5 μg/mL (100 μL/well). Dose-response curve for anti-HGF R antibody, hFc Tag with an EC₅₀ of 15.6 ng/mL determined by ELISA.

Immobilized Human HGF R SEMA Domain, His Tag at 2 μg/mL (100 μL/well). Dose-response curve for Human HGF, hFc Tag (Cat. HGF-HM201) with an EC₅₀ of 15.9 ng/mL determined by ELISA (QC test).

Product List

References

[1] Bradley, C., Salto-Tellez, M., Laurent-Puig, P. et al. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol 14, 562–576 (2017). https://doi.org/10.1038/nrclinonc.2017.40

[2]Uchikawa, E., Chen, Z., Xiao, GY. et al. Structural basis of the activation of c-MET receptor. Nat Commun 12, 4074 (2021). https://doi.org/10.1038/s41467-021-24367-3

[3]Yao HP, Tong XM, Wang MH. Pharmaceutical strategies in the emerging era of antibody-based biotherapeutics for the treatment of cancers overexpressing MET receptor tyrosine kinase. Drug Discov Today. 2021 Jan;26(1):106-121. doi: 10.1016/j.drudis.2020.11.002. Epub 2020 Nov 7. PMID: 33171292.

[4]Yao S, Liu X, Feng Y, Li Y, Xiao X, Han Y, Xia S. Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment. Int J Mol Sci. 2024 Aug 21;25(16):9101. doi: 10.3390/ijms25169101. PMID: 39201787; PMCID: PMC11354629.

[5] Fernandes M, Duplaquet L, Tulasne D. Proteolytic cleavages of MET: the divide-and-conquer strategy of a receptor tyrosine kinase. BMB Rep. 2019 Apr 30;52(4):239-249. doi: 10.5483/BMBRep.2019.52.4.024. PMID: 30670153; PMCID: PMC6507848.

[6]Zhang J, Babic A. Regulation of the MET oncogene: molecular mechanisms. Carcinogenesis. 2016 Apr;37(4):345-355. doi: 10.1093/carcin/bgw015. PMID: 26865268.

[7]Liu X, Sun R, Chen J, Liu L, Cui X, Shen S, Cui G, Ren Z, Yu Z. Crosstalk Mechanisms Between HGF/c-Met Axis and ncRNAs in Malignancy. Front Cell Dev Biol. 2020 Jan 31;8:23. doi: 10.3389/fcell.2020.00023. PMID: 32083078; PMCID: PMC7004951.

[8](PDF) Amivantamab: A Potent Novel EGFR/c-MET Bispecific Antibody Therapy for EGFR -mutated Non-small Cell Lung Cancer

[9]FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression | FDA

[10]Ji M, Ganesan S, Xia B, Huo Y. Targeting c-MET Alterations in Cancer: A Review of Genetic Drivers and Therapeutic Implications. Cancers. 2025; 17(9):1493. doi: 10.3390/cancers17091493

[11]Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021 Oct 20;39(30):3391-3402. doi: 10.1200/JCO.21.00662. PMID: 34339292; PMCID: PMC8713588.