Journal of Thoracic Oncology:
Pathway of the Month
MET Pathway as a Therapeutic Target
Kim, Eric S. MD; Salgia, Ravi MD, PhD
Section of Hematology/Oncology, Department of Medicine, and University of Chicago Cancer Research Center, University of Chicago Medical Center, Chicago, Illinois.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Ravi Salgia, MD, PhD, Section of Hematology/Oncology, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. E-mail: firstname.lastname@example.org
Dysregulation of mesenchymal-epithelial transition factor receptor tyrosine kinase pathway leads to cell proliferation, protection from apoptosis, angiogenesis, invasion, and metastasis. It can be dysregulated through overexpression, constitutive activation, gene amplification, ligand-dependent activation or mutation. New drugs targeting various mesenchymal-epithelial transition factor pathways are being investigated with promising results.
Many novel pathways critical to thoracic tumorigenesis are being identified and developed as potential therapeutic targets. Mesenchymal-epithelial transition factor (MET) receptor tyrosine kinase can be mutated or overexpressed in a number of epithelial human cancers, including lung and mesothelioma. It is activated by its ligand hepatocyte growth factor (HGF) and in malignant cells triggers a number of intracellular signaling transduction pathways resulting in alteration of biologic functions including metastasis.1–3
In this pathway review, we will highlight the basic biology of MET and current approaches to therapeutic targeting.
MET Structure and Pathway
MET was first discovered as an oncogene that encodes for the tyrosine kinase receptor for HGF. The gene for MET is located on chromosome 7q21-q31 and encodes for a single precursor that is posttranscriptionally digested and glycosylated, forming a 50 kDa extracellular α-chain and a transmembrane 140 kDa β-chain, which are linked by disulfide bonds. The MET β-chain contains homologous domains shared with other proteins, including a semaphorin (sema) domain, a PSI domain (in plexins, semaphorins and integrins), four IPT repeats (in immunoglobulins, plexins and transcription factors), a transmembrane domain, a juxtamembrane domain, a tyrosine kinase (TK) domain, and a carboxy-terminal tail region.4,5
MET’s ligand has been identified as HGF which is secreted by fibroblasts and smooth muscle cells.6 It binds MET’s sema domain and induces MET dimerization, autophosphorylation, and activation of tyrosine kinase catalytic activity.7,8 Tyrosine phosphorylation of JM, TK and tail domains respectively regulate internalization, catalytic activity, and docking of substrates such as Gab-1, Grb2, Shc, c-Cbl, which subsequently activate signal transducers such as PI3Kinase, PLC-γ, STAT, ERK1, ERK2, and FAK (Figure 1). Gab-1 is MET’s unique adaptor protein which mediates numerous MET-initiated signals.9–14 Gab-1 activates both the Erk and PI3K pathways. The Erk pathway regulates mitogenesis and the PI3K pathway regulates cell survival through the Akt/PKB pathway. Both pathways mediate cell adhesion, motility and invasion.15–17 Cell migration and invasion are mediated by Ras, Crk, and c-src/FAK, and branching morphogenesis further requires the STAT3 and PLC-γ pathways.18–22 Specifically, activation of Ras-Rac1/Cdc42-PAK and Gab1-Crk-C3G-Rap1 regulates cell adhesion and cytoskeletal proteins. Downstream molecules involved in the regulation of MET-induced motility and migration include cadherins, integrins, focal adhesion kinase, and paxillin.23 Of note, paxillin can be somatically mutated in lung cancer, and is an important downstream target of MET.24 Furthermore, MET signaling is involved in the regulation of tumor angiogenesis, either directly, through the proangiogenic activity of HGF that induces the formation of new vessels and the sprouting of the preexisting ones, or indirectly, through the regulated secretion of angiogenic factors, such as vascular endothelial growth factor A, interleukin-8, and thrombospondin-1.25–28
MET in Cancer
The regulation of MET can be influenced through overexpression, constitutive kinase activation, gene amplification, mutation, or paracrine/autocrine activation through HGF.29,30 It is previously shown that 67% of adenocarcinomas, 60% of carcinoids, 57% of large cell carcinomas, 57% of squamous cell carcinomas, and 25% of small cell lung cancer (SCLCs) strongly expressed MET.31 When assessing for functional activity with p-MET staining, 44% of adenocarcinomas, 86% of large cell, 71% of squamous cell, 40% of carcinoids, and 100% of SCLCs demonstrated MET phosphorylation at the Y1003 c-Cbl binding site; 33% of adenocarcinomas, 57% of large cell and 50% of SCLCs demonstrated MET autophosphorylation at the Y1230/1234/1235 site.31
A large number of missense mutations occur in the JM domains which are thought to be key regulators of receptor tyrosine kinases catalytic functions. Mutations at R988C, T1010I, and S1058P were identified in a study of 127 lung adenocarcinoma.31 Among these JM domain mutations, R988C and T1010I were previously found to enhance tumorigenicity, MET/downstream molecule phosphorylation and cell motility in SCLC.32 Mutations in the sema domain affect binding to HGF and those in the TK domain constitutively activated MET protein in hereditary papillary renal cell carcinomas.33 Besides missense mutations, MET-mediated tumorigenesis could be a result of gene amplification, leading to receptor overexpression. More recently, MET amplification was observed in approximately 20% of lung cancer specimens with acquired resistance to the epidermal growth factor receptor inhibitors.34,35 It is shown that amplification of MET causes gefitinib resistance by driving HER3-dependent activation of PI3K. Conversely, inhibition of MET signaling restored sensitivity to gefitinib.34 This observation further strengthens the hypothesis that MET activation contributes critically to tumor cell resistance.
Amplification of focal adhesion signaling molecules such as paxillin has also been demonstrated in lung cancer. Paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191).24
It is anticipated that targeted therapy against MET and its pathway will lead to significant inhibition of cancer growth and metastasis. The expression of MET protein has been targeted at the RNA levels with small interference RNA, microRNA, MET-specific ribozymes or at the level of protein maturation. Suppression of MET expression by delivering small interference RNA is a novel approach. SiRNA binds to ribosomes in place of MET RNA, effectively silencing MET RNA. MicroRNA is a form of single-stranded RNA that is thought to regulate gene expression by cleaving specific mRNA or by pairing with target mRNAs to silence their translation.36,37 Ribozymes are RNA-based enzymes that bind to and cleave RNA molecules in a sequence- specific manner. MET protein expression can be targeted at the level of protein maturation through inhibition of the heat shock protein (HSP90) by geldanamycin or members of the anisomycin antibiotic family.38
NK (N-terminal hairpin domain and Kringle domain) inhibitors form a family of four variants of HGF α-chain. NK4, a variant of HGF comprising only the four-kringles of the α-chain is a promising competitor for HGF. NK4 binds to MET without inducing receptor activation and thus behaves as a full antagonist.39 Moreover, as a consequence of its structural similarity to angiostatins, but independently from its effect on MET signaling, NK4 is able to inhibit angiogenesis induced by vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor.40 Similarly, the anti-HGF antibody binds an epitope in the β-chain of HGF and prevents it from binding to MET. In preclinical studies, this AMG102 (Amgen, Inc), a fully humanized monoclonal anti-HGF IgG showed good pharmacokinetic and safety profiles in cynomolgus monkeys41 and synergism with temozolomide and docetaxel in a U-87 MG (human glioblastoma derived containing HGF/MET autocrine loop cells) xenograft model in vivo.42 Phase I clinical trial with AMG 102 has been completed and phase II trials are currently being designed.
Several MET inhibitors are currently under investigation. Previously, a broad-spectrum kinase inhibitor at ATP binding site, K252a, was identified.43 Efforts to develop more specific inhibitors have led to characterization of SU11274 and PHA665752. At nanomolar concentrations, they are both at least 50-fold more selective for MET compared with other receptor tyrosine kinases and strongly inhibit HGF-induced activation of MET in cultured cells and tumorigenicity in mouse models.25,44,45 Most recently, PF2341066, an orally available selective competitor for MET has been shown to inhibit tumor cell growth in vitro and in vivo.46,47
There are a number of kinase inhibitors that have reached clinical trials.48 These include PF2341066, XL880 (Exelixis), XL184 (Exelixis), ARQ197 (ArQule Inc.), SGX523 (SGX Pharmaceuticals), and MGCD265 (MethylGene). SGX523 had to be stopped prematurely in phase I trial due to unexpected renal toxicity. Many of these inhibitors also have activity against other kinases. In the future, differentiation of MET inhibitors into specific kinase targets will need to be made. Determining specific patient subsets based on genetic profile that are more likely to respond to MET kinase inhibitors will contribute to better clinical outcome of these inhibitors. Lastly, as many tumors may require inhibition of more than one pathway, combinational strategies will need to be further explored.
Supported, in part, by NIH/NCI, American Lung Association, V-Foundation (Guy Geleerd Memorial Foundation), Kate McMullen Foundation, Respiratory Health Association of Chicago, and Mesothelioma Applied Research Foundation (Jeffrey P. Hayes Memorial Grant).
1. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science
2. Di Renzo MF, Narsimhan RP, Olivero M, et al. Expression of the Met/HGF receptor in normal and neoplastic human tissues. Oncogene
3. Benvenuti S, Comoglio PM. The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol
4. Maestrini E, Tamagnone L, Longati P, et al. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci U S A
5. Sattler M, Salgia R. c-Met and hepatocyte growth factor: potential as novel targets in cancer therapy. Curr Oncol Rep
6. Stella MC, Comoglio PM. HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol
7. Hammond DE, Urbe S, Vande Woude GF, Clague MJ. Down-regulation of MET, the receptor for hepatocyte growth factor. Oncogene
8. Peruzzi B, Bottaro DP. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res
9. Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature
10. Rodrigues GA, Park M. Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene
11. Ponzetto C, Bardelli A, Zhen Z, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell
12. Naldini L, Vigna E, Ferracini R, et al. The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation. Mol Cell Biol
13. Ma PC, Tretiakova MS, Nallasura V, Jagadeeswaran R, Husain AN, Salgia R. Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion. Br J Cancer
14. Sachs M, Brohmann H, Zechner D, et al. Essential role of Gab1 for signaling by the c-Met receptor in vivo. J Cell Biol
15. Day RM, Cioce V, Breckenridge D, Castagnino P, Bottaro DP. Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis. Oncogene
16. Fan S, Ma YX, Wang JA, et al. The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase. Oncogene
17. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR. Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A
18. Boccaccio C, Ando M, Tamagnone L, et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature
19. Chen HC, Chan PC, Tang MJ, Cheng CH, Chang TJ. Tyrosine phosphorylation of focal adhesion kinase stimulated by hepatocyte growth factor leads to mitogen-activated protein kinase activation. J Biol Chem
20. Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM. Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene
21. Lai JF, Kao SC, Jiang ST, Tang MJ, Chan PC, Chen HC. Involvement of focal adhesion kinase in hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells. J Biol Chem
22. Lamorte L, Kamikura DM, Park M. A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein. Oncogene
23. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol
24. Jagadeeswaran R, Surawska H, Krishnaswamy S, et al. Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. Cancer Res
25. Migliore C, Giordano S. Molecular cancer therapy: can our expectation be MET? Eur J Cancer
26. Gille J, Khalik M, Konig V, Kaufmann R. Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes. J Invest Dermatol
27. Zhang YW, Su Y, Volpert OV, Vande Woude GF. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci U S A
28. Rosen EM, Grant DS, Kleinman HK, et al. Scatter factor (hepatocyte growth factor) is a potent angiogenesis factor in vivo. Symp Soc Exp Biol
29. Furge KA, Kiewlich D, Le P, et al. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proc Natl Acad Sci U S A
30. Moghul A, Lin L, Beedle A, et al. Modulation of c-MET proto-oncogene (HGF receptor) mRNA abundance by cytokines and hormones: evidence for rapid decay of the 8 kb c-MET transcript. Oncogene
31. Ma PC, Jagadeeswaran R, Jagadeesh S, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res
32. Ma PC, Kijima T, Maulik G, et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res
33. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet
34. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science
35. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A
36. Kuhn DE, Martin MM, Feldman DS, Terry AV Jr, Nuovo GJ, Elton TS. Experimental validation of miRNA targets. Methods
37. Ross JS, Carlson JA, Brock G. miRNA: the new gene silencer. Am J Clin Pathol
38. Maulik G, Kijima T, Ma PC, et al. Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res
39. Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett
40. Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M, Nakamura T. HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res
41. Kakkar T, Ma M, Zhuang Y, Patton A, Hu Z, Mounho B. Pharmacokinetics and safety of a fully human hepatocyte growth factor antibody, AMG 102
, in cynomolgus monkeys. Pharm Res
42. Jun HT, Sun J, Rex K, et al. AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts. Clin Cancer Res
43. Morotti A, Mila S, Accornero P, Tagliabue E, Ponzetto C. K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene
44. Puri N, Khramtsov A, Ahmed S, et al. A selective small molecule inhibitor of c-Met, PHA665752
, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res
45. Berthou S, Aebersold DM, Schmidt LS, et al. The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene
46. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther
47. Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066
, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res
48. Abidoye O, Murukurthy N, Salgia R. Review of clinic trials: agents targeting c-Met. Rev Recent Clin Trials
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