Elsevier

Cancer Treatment Reviews

Volume 39, Issue 7, November 2013, Pages 793-801
Cancer Treatment Reviews

New Drugs
The emerging role of MET/HGF inhibitors in oncology

https://doi.org/10.1016/j.ctrv.2013.02.001Get rights and content

Abstract

The N-methyl-N′-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in many tumor types, can occur by multiple mechanisms, and promotes cellular proliferation and metastasis via growth factor receptors and other oncogenic receptor pathways. Thus, MET/HGF inhibition has emerged as targeted anticancer therapies. Preclinically, neoplastic and metastatic phenotypes of several tumor cells, including non-small cell lung cancer, hepatocellular carcinoma, and gastric cancer, were abrogated by MET inhibition. Ongoing clinical development with tivantinib, cabozantinib, onartuzumab, crizotinib, rilotumumab, and ficlatuzumab has shown encouraging results. These trials have established a key role for MET in a variety of tumor types. Evidence is emerging for identification of aberrant MET activity biomarkers and selection of patient subpopulations that may benefit from targeted MET and HGF inhibitor treatment.

Introduction

The N-methyl-N′-nitroso-guanidine human osteosarcoma transforming gene (MET) tyrosine kinase is the cell-surface receptor for hepatocyte growth factor (HGF, also known as scatter factor) that is involved in regulating cell proliferation, apoptosis, and migration.[1], [2], [3], [4] MET activity is normally detected in defined stages of embryogenesis and organogenesis.[5], [6], [7], [8], [9] In adults, MET appears to play a role in wound healing and response to organ damage.[10], [11], [12], [13] The MET pathway is also activated in degenerative diseases, including renal and lung fibrosis and cirrhosis.[14], [15], [16]

MET kinase activation results in activation of downstream signaling intermediates such as mitogen-activated protein kinase (MAPK), mammalian target of rapamycin pathway, and signal transducer and activator of transcription pathway.[2], [3], [17], [18] Signals generated from these assembled structures lead to changes in gene expression and cell behavior, with increased proliferation, survival, motility, invasiveness, and stimulation of angiogenesis.19

The MET pathway also engages in crosstalk with the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER) and KRAS signaling pathways, which are critical in the molecular pathogenesis of certain types of cancer, including non-small lung cancer (NSCLC) with intrinsic or acquired resistance to EGFR inhibitors.20

Aberrant MET expression is widely observed in solid and hematologic malignancies.21 Cellular deregulation of MET can occur through mechanisms including MET-receptor overexpression, genomic amplification, mutation, or alternative splicing.[2], [3], [22] These disruptions in normal MET signaling lead to dysregulation of the MET pathway via autocrine, paracrine, or endocrine feedback signaling cascades, inducing disruption of intercellular contacts, promoting cell migration, inhibiting detachment-mediated apoptosis, and resulting in colonization and proliferation of cells at remote sites.[3], [18], [23]

MET was originally identified as the protein product of the translocated promoter region (TPR)-MET transforming oncogene, which was derived from an osteosarcoma cell line.24 The oncogenic TPR-MET fusion protein was demonstrated to have constitutive enzymatic activity that led to development of spontaneous mammary hyperplasia and tumors.25 In other preclinical models, TPR-MET transduction via lentiviral vectors in the livers of adult mice led to slowly progressing hepatocarcinogenesis.26 In humans, TPR-MET chromosomal rearrangement has been detected in gastric cancer tumor tissue.27

Section snippets

Search strategy and selection criteria

References for this review were identified through searches of PubMed with the search terms “MET inhibitor” and “c-met inhibitor.” Additional references were obtained from the reference sections of articles identified using these search terms. In addition, abstracts from annual meetings of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and American Association for Cancer Research (AACR) were searched to identify recent presentations related to

Role of met in tumor biology

MET amplification has been reported in a number of human primary tumors, including gastric and esophageal cancer, medulloblastoma, and NSCLC with acquired resistance to EGFR inhibitors (Table 1).[2], [21], [28] In animal models, conditional MET overexpression in hepatocytes results in development of hepatocellular carcinoma (HCC) that regresses when the transfected gene is inactivated.29 In patients with colorectal cancer (CRC), MET amplification was reported in a higher percentage of liver

Resistance to met inhibitors

As the clinical development of MET inhibitors progresses, experience with tyrosine kinase inhibitors (TKIs) that target other RTKs suggests that patients with tumors that initially respond to MET inhibitors may eventually develop resistance. Acquired resistance of NSCLC to EGFR inhibitors via MET amplification has been demonstrated experimentally and clinically; however, less is known about mechanisms of resistance to MET inhibitors. In a recent study using a MET-dependent gastric cancer cell

Met and lung cancer

In tumor microarray analysis of human cancers, MET and HGF were most commonly expressed in lung tumors (72%).72 Analysis of tyrosine kinase signaling in NSCLC cell lines and tumor samples also demonstrated that MET is the most highly phosphorylated RTK in NSCLC tumor samples, providing additional evidence of the key role of MET in NSCLC.[72], [73]

MET amplification is a rare event in lung cancer, occurring in 4–21% of patients with NSCLC and up to 4% of patients with adenocarcinoma, and is

Clinical development of met inhibitors

Increased understanding of the structure–function relationship of MET and HGF has led to development of several MET and HGF inhibitors. Major classes of MET/HGF inhibitors include monoclonal antibodies (mAbs) that bind HGF or compete with HGF for binding to MET and selective and nonselective MET TKIs (Table 2, Table 3). MET inhibitors are under investigation both as monotherapy or combined with other targeted agents or chemotherapy for the treatment of a wide variety of tumors. Specific tumor

Discussion

The MET pathway has emerged to play a central role in human cancer. Aberrant MET/HGF expression is observed in numerous types of cancer and is associated with a poor prognosis. A more focused understanding of the role of the MET pathway in tumor biology has provided the rationale for clinical development of targeted inhibitors of MET in a variety of tumor types. The MET inhibitors that have progressed furthest in clinical development are all being investigated in patients with NSCLC, although

Conflicts of interest statement

G.V.S. has received honoraria from Eli Lilly, AstraZeneca, Roche, and Pfizer; S.N. has no conflicts of interest to disclose; J.v.P. has served as a consultant for Daiichi Sankyo.

Role of the funding source

Financial support for medical editorial assistance was provided by Daiichi Sankyo, Inc.

Acknowledgments

We thank Bret Wing, PhD, of Accuverus, for his medical editorial assistance with this manuscript.

References (124)

  • K. Rikova et al.

    Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer

    Cell

    (2007)
  • M. Beau-Faller et al.

    MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naive cohort

    J Thorac Oncol

    (2008)
  • H. Go et al.

    High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer

    J Thorac Oncol

    (2010)
  • T. Onitsuka et al.

    Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status

    J Thorac Oncol

    (2010)
  • R. Dziadziuszko et al.

    Correlation between MET gene copy number by silver in situ hybridization and protein expression by immunohistochemistry in non-small cell lung cancer

    J Thorac Oncol

    (2012)
  • M.S. Tsao et al.

    Differential expression of Met/hepatocyte growth factor receptor in subtypes of non-small cell lung cancers

    Lung Cancer

    (1998)
  • K. Tsuta et al.

    C-MET/Phospho-MET protein expression and MET gene copy number in non-small cell lung carcinomas

    J Thorac Oncol

    (2012)
  • A.B. Turke et al.

    Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC

    Cancer Cell

    (2010)
  • S. Eathiraj et al.

    Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal–epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197

    J Biol Chem

    (2011)
  • G.V. Scagliotti et al.

    Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer

    Clin Lung Cancer

    (2012)
  • A. Santoro et al.

    Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomized, placebo-controlled phase 2 study

    Lancet Oncol

    (2013)
  • C. Birchmeier et al.

    Met, metastasis, motility and more

    Nat Rev Mol Cell Biol

    (2003)
  • P.M. Comoglio et al.

    Drug development of MET inhibitors: targeting oncogene addiction and expedience

    Nat Rev Drug Discov

    (2008)
  • E. Gherardi et al.

    Targeting MET in cancer: rationale and progress

    Nat Rev Cancer

    (2012)
  • L. Trusolino et al.

    MET signalling: principles and functions in development, organ regeneration and cancer

    Nat Rev Mol Cell Biol

    (2010)
  • E. Andermarcher et al.

    Co-expression of the HGF/SF and c-met genes during early mouse embryogenesis precedes reciprocal expression in adjacent tissues during organogenesis

    Dev Genet

    (1996)
  • F. Bladt et al.

    Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud

    Nature

    (1995)
  • F. Bussolino et al.

    Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

    J Cell Biol

    (1992)
  • A. Streit et al.

    A role for HGF/SF in neural induction and its expression in Hensen’s node during gastrulation

    Development

    (1995)
  • H. Takayama et al.

    Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development

    Proc Natl Acad Sci U S A

    (1996)
  • G.K. Michalopoulos et al.

    Liver regeneration

    Science

    (1997)
  • T. Nakamura et al.

    Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF

    J Clin Invest

    (2000)
  • C. Schmidt et al.

    Scatter factor/hepatocyte growth factor is essential for liver development

    Nature

    (1995)
  • T. Ueki et al.

    Hepatocyte growth factor gene therapy of liver cirrhosis in rats

    Nat Med

    (1999)
  • K.M. Weidner et al.

    Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis

    Nature

    (1996)
  • L.J. Appleman

    MET signaling pathway: a rational target for cancer therapy

    J Clin Oncol

    (2011)
  • Van Andel Institute. Hepatocyte growth factor/scatter factor (HGF/SF), MET and cancer references; 2012....
  • G.H. Xiao et al.

    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

    (2001)
  • C.S. Cooper et al.

    Molecular cloning of a new transforming gene from a chemically transformed human cell line

    Nature

    (1984)
  • T.J. Liang et al.

    Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors

    J Clin Invest

    (1996)
  • C. Boccaccio et al.

    The MET oncogene drives a genetic programme linking cancer to haemostasis

    Nature

    (2005)
  • N.R. Soman et al.

    The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions

    Proc Natl Acad Sci U S A

    (1991)
  • M. Sattler et al.

    The role of the c-Met pathway in lung cancer and the potential for targeted therapy

    Ther Adv Med Oncol

    (2011)
  • R. Wang et al.

    Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice

    J Cell Biol

    (2001)
  • M.F. Di Renzo et al.

    Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer

    Clin Cancer Res

    (1995)
  • J.H. Lee et al.

    A novel germ line juxtamembrane Met mutation in human gastric cancer

    Oncogene

    (2000)
  • W.S. Park et al.

    Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas

    Cancer Res

    (1999)
  • L. Schmidt et al.

    Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas

    Nat Genet

    (1997)
  • F. Graziano et al.

    Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer

    J Clin Oncol

    (2011)
  • T.K. Choueiri et al.

    Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma

    J Clin Oncol

    (2013)
  • Cited by (0)

    c

    Tel.: +39 011 9026 539/978.

    d

    Tel.: +49 89 857912011.

    View full text