Elsevier

The Lancet Oncology

Volume 10, Issue 7, July 2009, Pages 709-717
The Lancet Oncology

Review
Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors

https://doi.org/10.1016/S1470-2045(09)70137-8Get rights and content

Summary

The hepatocyte growth factor (HGF)–mesenchymal-epithelial transition factor (MET) pathway has a key role in carcinogenesis; it is implicated in proliferation, inhibition of apoptosis, angiogenesis, migration, invasiveness, and metastasis. All of these molecular events are driven through membrane and intracellular coplayers and several downstream effector proteins. MET has been shown to cross react with epithelial growth factor receptor (EGFR) proteins and possibly substitutes their activity, thus conferring resistance to EGFR-targeting drugs. Therefore, identification of MET inhibitors might lead to new treatments for MET-triggered neoplasia and improve the sensitivity of molecularly targeted antineoplastic compounds that are currently in use. In this Review, we outline current data regarding the HGF–MET pathway during carcinogenesis and the strategies for therapeutic targeting of this pathway. We also discuss the rationale and future perspectives of the combinatorial blockade of HGF–MET and EGFR signalling cascades in cancer treatment.

Introduction

The dissociation and migration of tumour cells, their adhesive interactions with the extracellular matrix, and the proteolysis of extracellular matrix proteins have a key role in tumour progression and metastasis. Deregulation of membrane receptors with tyrosine-kinase activity leads to malignant transformation and resistance to novel anticancer therapies. The hepatocyte growth factor (HGF)–mesenchymal-epithelial transition factor (MET) molecular pathway affects cancer development at different stages, from initiation to metastatic behaviour, in many tumour types.

The epidermal growth factor receptor (EGFR), or ERBB, family is important in carcinogenesis. Among its members, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (ERBB2) are now successfully targeted by biological agents used in cancer therapeutics.1, 2 However, their effectiveness is limited in some patients because of the development of intrinsic or acquired resistance, and there is a need to identify other molecular participants in ERBB-related cellular events. In in-vitro studies of cancer cell lines, cells with an increased gene copy number of EGFR and ERBB2 are dependent on that gene for growth and survival. Some human cancers, such as lung and gastric carcinomas and rhabdomyosarcomas, are also dependent on MET receptor as an absolute requirement for their development and progression.3, 4 MET-related signal transduction is thought to be involved in the development of resistance to EGFR-targeting agents.5, 6, 7

We review the role of MET in carcinogenesis—including strategies to block its pathway in combination with current treatment modalities, especially with anti-EGFR-targeting agents, and consider future perspectives of this rationale in cancer therapeutics.

Section snippets

MET pathway and carcinogenesis

MET was first identified as the protein product of a transforming oncogene, in cultured human osteosarcoma cells (figure 1).8 Isolation of the full-length MET oncogene coding sequence revealed structural features of a membrane receptor with tyrosine-kinase activity.9 HGF, also known as scatter factor, was identified as the natural ligand of MET receptor.10

HGF and MET proteins are processed proteolytically from single-chain precursors into mature disulphide-linked heterodimers. MET is normally

Crosstalk between MET and tyrosine-kinase membrane receptors

MET receptor interacts with other membrane receptors, and many different molecules act as MET partners, including integrin α6β4, the adhesive molecule CD44, class B plexins, FAS, and other tyrosine-kinase receptors such as RON (recepteur d'origine nantais), EGFR, and ERBB2 (figure 3).

Receptors with tyrosin-kinase activity that interact with MET include RON, also known as stem-cell-derived tyrosine kinase in mice.33 RON displays 25% homology with MET in the extracellular region and 63% homology

Strategies for targeting HGF–MET

Various strategies are currently in development to disrupt the HGF–MET signal transduction pathway. Most are being assessed in preclinical animal models or are entering early clinical testing. Before these treatments proceed to large-scale clinical trials, their antitumour activity as a single therapeutic strategy or in combination with other molecularly targeted agents (mainly EGFR inhibitors) should be established, and concerns regarding toxic effects in healthy tissues (eg, liver

EGFR-directed agents

Although the blockade of EGFR function can be accomplished by several methods, two approaches have been most extensively studied: MoAbs against the extracellular receptor domain and small-molecule EGFR-tyrosine-kinase inhibitors.1 However, the clinical application of these compounds has created a number of challenges. The mechanisms of intrinsic or acquired resistance to anti-EGFR therapy are unknown, although many molecular events have been implicated.58 Cumulative evidence suggests that a

Future perspectives

The HGF–MET pathway is a promising target for the development of novel antineoplastic biological agents. Cancers triggered by MET downstream stimuli are governed by different molecular abnormalities. The heterogeneity that characterises MET-related carcinogenesis, along with the documented cross reactions with other membrane-initiated molecular routes, warrants well designed preclinical strategies for finding the best methods of HGF–MET inhibition in human carcinomas. Furthermore, the

Search strategy and selection criteria

References for this Review were found through a search of Pubmed and Medline (January, 1966, to January, 2009), Cochrane Library (January, 1990, to January, 2009) and Embase (January, 1998, to January, 2009). Search terms included “cancer”, “lung cancer”, “breast cancer”, “malignant gliomas”, “gastric cancer”, “MET receptor”, “hepatocyte growth factor”, “scatter factor”, “RON”, “invasive growth”, “metastatic cascade”, “clinical trials”, “EGFR”, “ERBB2”, “ERBB3”, “ERBB4”, “chemotherapy”,

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      c-Met belongs to a subfamily of receptor tyrosine kinases (RTKs) encoded by the c-Met proto-oncogene, which was discovered in human osteosarcoma cell lines [9,10]. The binding of hepatocyte growth factor (HGF) to c-Met induces a series of effects, including proliferation, angiogenesis, invasion and migration, which are essential in normal physiology [11,12]. However, the abnormal activation of c-Met occurs in many types of human cancers, such as breast, liver, gastric cancers and so on [13–15].

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