Project

Back to overview

The link between aberrant MET signaling and DNA repair pathways in liver tumor cells as a target for sensitization to DNA damaging agents

Applicant Zimmer Yitzhak
Number 125394
Funding scheme Project funding (Div. I-III)
Research institution Department for BioMedical Research Forschungsgruppe Radio-Onkologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Radiobiology
Start/End 01.01.2010 - 31.12.2013
Approved amount 288'000.00
Show all

Keywords (8)

receptor tyrosine kinase; MET; DNA damage; DNA repair; Hepatocellular carcinoma; HCC; DNA damage repair; small molecule inhibitors

Lay Summary (English)

Lead
Lay summary
The relevance of aberrant function of the MET receptor tyrosine kinase to the pathogenesis of a broad spectrum of human malignancies has been firmly established over the last three decades and studies with first generation anti MET small molecule inhibitors strongly support the expectations of MET for becoming a central molecular target in cancer therapy, primarily of solid tumors.Apart of playing cardinal roles in the biology of cancer onset and maintenance, increasing data indicate that MET signaling may couple to the cellular DNA damage response machinery. This can eventually result in the shielding of tumor cells from cytotoxicity induced by therapeutical modalities, which largely act by inflicting DNA damage, such as ionizing radiation and radiomimetic drugs. In this respect, a recent work from our lab has shown that MET mutants are exclusively able to switch and activate a novel molecular axis that couples MET to DNA repair via homologous recombination.Hepatocellular carcinoma is a major malignant liver tumor in which deregulated MET expression has been documented. These tumors are commonly resistant to conventional chemotherapy, while radiation therapy is usually not applicable due to high toxicity towards normal liver tissue.Due to the emerging link between MET and DNA repair, the significance of the MET/hepatocyte growth factor axis to the pathogenesis of liver cancers whose incidence worldwide is constantly increasing and because the current therapeutic options for hepatocellular carcinoma patients are sobering, we focus mainly on the potential link between deregulated MET activity in liver models for these liver tumors and subsequent activation of DNA repair pathways. In addition, we study MET inhibition by small molecules as a means of increasing the sensitivity of these tumor cells towards DNA damaging agents. The major goal of this study is to provide an evidence for the relevance of the MET system to the activation of the DNA damage response in a tumor with high clinical significance and to develop experimental sensitization protocols with hopefully clinical applicative horizons.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.
Leiser Dominic, Pochon Benoit, Blank-Liss Wieslawa, Francica Paola, Glueck Astrid Andreina, Aebersold Daniel Matthias, Zimmer Yitzhak, Medova Michaela (2014), Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation., in FEBS Letters, 588(5), 653-658.
The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response-Biological and Clinical Aspects.
Medova Michaela, Aebersold Daniel Matthias, Zimmer Yitzhak (2014), The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response-Biological and Clinical Aspects., in Cancers, 6(1), 1-27.
Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells
Humbert Magali, Medova Michaela, Aebersold Daniel Matthias, Blaukat Andree, Bladt Friedhelm, Fey Martin F, Zimmer Yitzhak, Tschan Mario P (2013), Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells, in Biochem Biophys Res Commun, 431(2), 264-269.
The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants.
Medova Michaela, Pochon Benoit, Streit Bruno, Blank-Liss Wieslawa, Francica Paola, Stroka Deborah, Keogh Adrian, Aebersold Daniel Matthias, Blaukat Andree, Bladt Friedhelm, Zimmer Yittzhak (2013), The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants., in Molecular Cancer Therapeutics, 12(11), 2415-2424.
MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks.
Medova Michaela, Aebersold Daniel Matthias, Zimmer Yitzhak (2012), MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks., in International Journal of Cancer, 130(3), 728-734.
Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer
Nisa Lluis, Aebersold Daniel Matthias, Giger Roland, Zimmer Yitzhak, Medova Michaela, Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, in Pharmacology & Therapeutics.

Collaboration

Group / person Country
Types of collaboration
Merck Darmstadt Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
AlumniMed Bern Preis 2011

Associated projects

Number Title Start Funding scheme
145003 A new Zeiss LSM 710 laser scanning microscope for the DCR LCI Core Facility 01.12.2012 R'EQUIP
156816 Impact of MET receptor tyrosine kinase inhibition on the DNA damage response-related phosphoproteome 01.12.2014 Project funding (Div. I-III)
139231 Advancement of functional genomics research at the University of Bern by extension of LC-MS platform 01.07.2012 R'EQUIP

Abstract

The relevance of aberrant function of the MET receptor tyrosine kinase for hepatocyte growth factor to malignant cellular transformation and to the pathogenesis of a broad spectrum of human malignancies has been firmly established over the last three decades. MET oncogenic activity may be unleashed by various molecular mechanisms such as overexpression, autocrine and paracrine deregulated loops and point mutations. Studies from recent years with first generation anti MET small molecule inhibitors strongly support the expectations of MET for becoming a central molecular target in cancer therapy, primarily of solid tumors. Apart of playing cardinal roles in the biology of cancer onset and maintenance, increasing data indicate that MET signaling originating either from the wild type receptor or from its mutated variants, may couple to the cellular DNA damage response machinery. This can eventually result in the shielding of tumor cells from cytotoxicity induced by therapeutical modalities, which largely act by inflicting DNA damage, such as ionizing radiation and radiomimetic drugs. In this respect, a recent work from our lab has shown that MET mutants are exclusively able to switch and activate a novel molecular axis that couples MET to DNA repair via homologous recombination.Hepatocellular carcinoma is a major malignant liver tumor in which deregulated MET expression has been documented. These tumors are commonly resistant to conventional chemotherapy, including agents such as adriamycin that causes DNA damage by eliciting double strand DNA breaks, while radiation therapy is usually not applicable due to high toxicity towards normal liver tissue.Due to the emerging link between MET and DNA repair, the significance of the MET/hepatocyte growth factor axis to the pathogenesis of liver cancers whose incidence worldwide is constantly increasing and because the current therapeutic options for hepatocellular carcinoma patients are sobering, we aim in the current proposed study to focus mainly on the potential link between deregulated MET activity in liver models for these liver tumors and subsequent activation of DNA repair pathways and to explore MET inhibition as a means of increasing the sensitivity of these tumor cells towards DNA damaging agents. The major goal of this study is to provide an evidence for the relevance of the MET system to the activation of the DNA damage response in a tumor with high clinical significance and to develop experimental sensitization protocols with hopefully clinical applicative horizons. Here we propose to dissect in details the link between MET deregulated function and DNA repair pathways in two different cellular models of hepatocellular carcinoma:1.The well-established rat Morris Hepatoma system.2.A model of mouse primary hepatocytes originating from transgenic mouse line FVB.129S6-Gt(ROSA), which will be established by transduction of lentiviral vectors that drive the expression of wild type and mutated/oncogenic MET constructs. The specific aims of the current study are:A.In vitro characterization of the impact of aberrant MET expression on the primary liver cells phenotype following transduction by MET lentiviral vectors in terms of differentiation and features of malignant transformation.B.In vitro characterization of the potential MET-dependent activation of DNA repair pathways in the primary MET-transduced liver cells and study of their responsiveness to DNA damaging agents in presence or absence of a MET small molecule inhibitor and in comparison with Morris Hepatoma cells.Establishment of in vivo models for hepatocellular carcinoma and tumor responsiveness to DNA damaging agents. In this part, various experimental protocols that combine MET inhibition with the radiomimetic drug adriamycin (doxorubicin) will be studied.
-