Chordoma Foundation

c-MET

Mesenchymal Epithelial Transition Factor (c-MET, also known as Hepatocyte Growth Factor Receptor) is a receptor tyrosine kinase (RTK). RTKs code for proteins on the surface of the cell that become activated when bound by their ligand.

Ligands: HGF
Location: Chromosome 7q31

Binding of HGF to c-Met
activates a number of signaling pathways linked to cellular processes of growth, invasion, and morphogenic differentiation. HGF/c-MET interacts with both the PI3k-Akt-mTOR and RAS-RAF-MEK-MAPK pathways.

c-MET in Chordoma

The c-MET gene first received the attention of chordoma researchers because it resides on a region of chromosome 7 that is frequently exhibits abnormalities in chordoma cells. The c-MET protein is strongly expressed in many chordomas and has been linked to better prognosis in certain types of chordoma. c-MET and its ligand, HGF, are targets for the treatment of other cancers, leading researchers to ask whether they could be targeted to treat chordoma. This page contains a summary of their ongoing exploration of the role of c-MET/HGF in chordoma.

Molecular Evidence


Copy Number Variation

  • Chromosomal Aberrations: Abnormalities involving chromosome 7, where c-MET resides, are among the most common aberrations detected in chordoma.1 2 3 4 5 6
  • c-MET Gene Copy Number Variation: c-MET gene amplification does not appear to be responsible for the gene’s overexpression.4

Gene Expression

  • c-MET gene expression is higher in chordoma than in fetal nucleus pulposus control tissue.7

Protein Expression

  • c-MET protein is detected in nearly all chordoma samples tested.8 9 10 HGF, its ligand, is sparsely detected, indicating that a paracrine rather than an autocrine regulatory loop is at work.4 5 11 12 13 14 15 16 17 18
  • c-Met expression has been shown to have prognostic value in chordoma. One study of 71 chordoma patients found that 79.9% of patients expressing c-MET survived at least 5 years while only 44.4% of those not expressing c-MET survived at least 5 years.15 Another study of 52 spinal chordoma patients found that patients with higher levels of c-Met expression  had a significantly better prognosis than those with lower c-Met expression. It also showed that expression was significantly higher in older patients than in younger patients.17 However, a smaller study found a significant correlation between positive c-MET expression and recurrence.19
  • miRNA-1, thought to target c-MET expression, was found to be significantly downregulated in 93.7% of chordoma samples. This downregulation was concomitant with increased c-MET expression in 78% of samples, suggesting a role for miRNA-1 in regulating c-MET expression.20
  • c-Met protein levels are inversely correlated with miRNA-34a expression and miRNA-34a is downregulated in chordoma cell lines. c-Met is predicted to be a target of miRNA-34a in chordoma.21

Protein Activation

  • Phosphorylation of the c-MET protein is enhanced upon the binding of HGF.22

Preclinical Evidence


In-vitro Efficacy

  • miRNA therapy: miRNAs that target c-MET are significantly downregulated in chordoma. Two of them, miRNA-1 and miRNA-31, have been shown to reduce chordoma cell growth and promote apoptosis when overexpressed in chordoma cell lines.14 20 23 24
  • Sapatinib + Crizotinib: In a study of EGFR inhibitors in seven chordoma cell lines, c-MET signaling was activated in the most resistant cell line (U-CH2). A combination of the EGFR inhibitor sapitinib and the c-MET-inhibitor crizotinib exhibited a synergistic effect on cell kill.18
  • Crizotinib and miRNA-34a: Transfection of chordoma cell lines with pre-miRNA-34a inhibited cell proliferation, survival and invasion similar to treatment with Crizotinib.21
  • Crizotinib, cabozantinib, PHA-665752: Treatment of a panel of six chordoma cell lines with each of these MET inhibitors did not result in anti-proliferative activity.10

Clinical Evidence


Case Report

  • Crizotinib: A patient was found to have a c-MET mutation after recurrence. Treatment with c-MET/HGFR inhibitor Crizotinib led to 17 months progression-free survival and disappearance of the mutation.25


References

1.
Brandal P, Bjerkehagen B, Danielsen H, Heim S. Chromosome 7 abnormalities are common in chordomas. Cancer Genet Cytogenet. 2005;160(1):15-21. [PubMed]
2.
Sawyer J, Husain M, Al-Mefty O. Identification of isochromosome 1q as a recurring chromosome aberration in skull base chordomas: a new marker for aggressive tumors? Neurosurg Focus. 2001;10(3):E6. [PubMed]
3.
Scheil S, Brüderlein S, Liehr T, et al. Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Genes Chromosomes Cancer. 2001;32(3):203-211. [PubMed]
4.
Grabellus F, Konik M, Worm K, et al. MET overexpressing chordomas frequently exhibit polysomy of chromosome 7 but no MET activation through sarcoma-specific gene fusions. Tumour Biol. 2010;31(3):157-163. [PubMed]
5.
Walter B, Begnami M, Valera V, Santi M, Rushing E, Quezado M. Gain of chromosome 7 by chromogenic in situ hybridization (CISH) in chordomas is correlated to c-MET expression. J Neurooncol. 2011;101(2):199-206. [PubMed]
6.
Scheil-Bertram S, Kappler R, von B, et al. Molecular profiling of chordoma. Int J Oncol. 2014;44(4):1041-1055. [PubMed]
7.
Chen H, Zhang K, Lu J, Wu G, Yang H, Chen K. Comprehensive analysis of mRNA-lncRNA co-expression profile revealing crucial role of imprinted gene cluster DLK1-MEG3 in chordoma. Oncotarget. 2017;8(68):112623-112635. [PMC]
8.
Akhavan-Sigari R, Abili M, Gaab M, et al. Immunohistochemical expression of receptor tyrosine kinase PDGFR-α, c-Met, and EGFR in skull base chordoma. Neurosurg Rev. 2015;38(1):89-98; discussion 98-9. [PubMed]
9.
Bosotti R, Magnaghi P, Di B, et al. Establishment and genomic characterization of the new chordoma cell line Chor-IN-1. Sci Rep. 2017;7(1):9226. [PubMed]
10.
Magnaghi P, Salom B, Cozzi L, et al. Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury. Mol Cancer Ther. December 2017. [PubMed]
11.
Naka T, Iwamoto Y, Shinohara N, Ushijima M, Chuman H, Tsuneyoshi M. Expression of c-met proto-oncogene product (c-MET) in benign and malignant bone tumors. Mod Pathol. 1997;10(8):832-838. [PubMed]
12.
Weinberger P, Yu Z, Kowalski D, et al. Differential expression of epidermal growth factor receptor, c-Met, and HER2/neu in chordoma compared with 17 other malignancies. Arch Otolaryngol Head Neck Surg. 2005;131(8):707-711. [PubMed]
13.
Naka T, Boltze C, Samii A, et al. Expression of c-MET, low-molecular-weight cytokeratin, matrix metalloproteinases-1 and -2 in spinal chordoma. Histopathology. 2009;54(5):607-613. [PubMed]
14.
Duan Z, Choy E, Nielsen G, et al. Differential expression of microRNA (miRNA) in chordoma reveals a role for miRNA-1 in Met expression. J Orthop Res. 2010;28(6):746-752. [PubMed]
15.
Naka T, Kuester D, Boltze C, et al. Expression of hepatocyte growth factor and c-MET in skull base chordoma. Cancer. 2008;112(1):104-110. [PubMed]
16.
de C, Guimaraes G, Aguiar S, et al. Tyrosine kinase receptor expression in chordomas: phosphorylated AKT correlates inversely with outcome. Hum Pathol. 2013;44(9):1747-1755. [PubMed]
17.
Akhavan-Sigari R, Gaab M, Rohde V, Abili M, Ostertag H. Expression of PDGFR-α, EGFR and c-MET in spinal chordoma: a series of 52 patients. Anticancer Res. 2014;34(2):623-630. [PubMed]
18.
Scheipl S, Barnard M, Cottone L, et al. EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen. J Pathol. 2016;239(3):320-334. [PubMed]
19.
Tosuner Z, Bozkurt S, Kiliç T, Yilmaz B. The Role of EGFR, Hepatocyte Growth Factor Receptor (c-Met), c-ErbB2 (HER2-neu) and Clinicopathological Parameters in the Pathogenesis and Prognosis of Chordoma. Turk Patoloji Derg. 2017;33(2):112-120. [PubMed]
20.
Duan Z, Shen J, Yang X, et al. Prognostic significance of miRNA-1 (miR-1) expression in patients with chordoma. J Orthop Res. 2014;32(5):695-701. [PubMed]
21.
Zhang Y, Schiff D, Park D, Abounader R. MicroRNA-608 and MicroRNA-34a Regulate Chordoma Malignancy by Targeting EGFR, Bcl-xL and MET. PLoS One. 2014;9(3):e91546. [PMC]
22.
Ostroumov E, Hunter C. Identifying mechanisms for therapeutic intervention in chordoma: c-Met oncoprotein. Spine (Phila Pa 1976). 2008;33(25):2774-2780. [PubMed]
23.
Bayrak O, Gulluoglu S, Aydemir E, et al. MicroRNA expression profiling reveals the potential function of microRNA-31 in chordomas. J Neurooncol. 2013;115(2):143-151. [PubMed]
24.
Gulluoglu S, Tuysuz E, Kuskucu A, et al. The potential function of microRNA in chordomas. Gene. 2016;585(1):76-83. [PubMed]
25.
Liang W S, Millis S Z, Gatalica Z, Reddy S K, Little A, Van Tine B A. Identification of actionable targets in chordomas using a multiplatform molecular analysis, and response with targeted therapy [abstract]. 2015 ASCO Annual Meeting. http://meetinglibrary.asco.org/record/111630/abstract. Published 2015.