The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response—Biological and Clinical Aspects

Michaela Medová,Daniel Aebersold,Yitzhak Zimmer

doi:10.3390/cancers6010001

Michaela Medová, Daniel Aebersold + Show 1 more

Open Access

https://doi.org/10.3390/cancers6010001

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Journal: Cancers	Publication Date: Dec 19, 2013
Citations: 32	License type: CC BY 4.0

Affiliation: University of Bern, University Hospital of Bern

Abstract

Radiation therapy remains an imperative treatment modality for numerous malignancies. Enduring significant technical achievements both on the levels of treatment planning and radiation delivery have led to improvements in local control of tumor growth and reduction in healthy tissue toxicity. Nevertheless, resistance mechanisms, which presumably also involve activation of DNA damage response signaling pathways that eventually may account for loco-regional relapse and consequent tumor progression, still remain a critical problem. Accumulating data suggest that signaling via growth factor receptor tyrosine kinases, which are aberrantly expressed in many tumors, may interfere with the cytotoxic impact of ionizing radiation via the direct activation of the DNA damage response, leading eventually to so-called tumor radioresistance. The aim of this review is to overview the current known data that support a molecular crosstalk between the hepatocyte growth factor receptor tyrosine kinase MET and the DNA damage response. Apart of extending well established concepts over MET biology beyond its function as a growth factor receptor, these observations directly relate to the role of its aberrant activity in resistance to DNA damaging agents, such as ionizing radiation, which are routinely used in cancer therapy and advocate tumor sensitization towards DNA damaging agents in combination with MET targeting.

Highlights

The receptor tyrosine kinase (RTK) MET is the cell surface receptor for hepatocyte growth factor (HGF) and is primarily expressed on epithelial cells of many organs during embryogenesis and in adulthood, including the liver, pancreas, prostate, kidney, muscle, and bone marrow [1,2]
Treatment failure, due to resistance mechanisms, which presumably involve activation of DNA damage response (DDR) signaling pathways that account for loco-regional relapse and consequent tumor progression still remain a critical problem [28]
Radiation therapy (RT) affects healthy tissue as well, normal cells can usually repair more effectively DNA damage via the activation of repair as well as checkpoint controls machineries, which are severely compromised in cancer cells [26]

Summary

Introduction

The receptor tyrosine kinase (RTK) MET is the cell surface receptor for hepatocyte growth factor (HGF) and is primarily expressed on epithelial cells of many organs during embryogenesis and in adulthood, including the liver, pancreas, prostate, kidney, muscle, and bone marrow [1,2]. MET was first identified as an oncogene in 1984 as part of a rare translocation with the nucleoporin translocated promoter region gene (TPR) giving rise to the TPR-MET chimeric oncoprotein [1]. Since this first observation, a variety of additional oncogenic mechanisms that lead to aberrant MET signaling such as overexpression of HGF and/or MET, MET gene amplification and point mutations have been described and extensively characterized in preclinical models [3]. In vivo studies have shown that activation of the HGF/MET signaling promotes cell invasiveness and triggers metastases through direct involvement in regulation of angiogenesis [4]

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