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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Targeting the MET receptor tyrosine kinase as a strategy for radiosensitization in loco-regionally advanced head and neck squamous cell carcinoma

Lluís Nisa, Paola Francica, Roland Giger, Matúš Medo, Olgun Elicin, Manja Friese-Hamim, Claudia Wilm, Christopher Stroh, Beat Bojaxhiu, Aurélie Quintin, Marco D Caversaccio, Matthias S. Dettmer, Mélanie Buchwalder, Tess M. Brodie, Daniel M Aebersold, Yitzhak Zimmer, Thomas E. Carey and Michaela Medová
Lluís Nisa
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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Paola Francica
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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Roland Giger
Universitätsklinik für HNO, Kopf- und Halschirurgie, Inselspital, Bern University Hospital, and University of Bern
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Matúš Medo
Dept. of Physics, University of Fribourg
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Olgun Elicin
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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  • ORCID record for Olgun Elicin
Manja Friese-Hamim
Translational Innovation Platform Oncology, Merck HealthCare KGaA
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Claudia Wilm
Translational Innovation Platform Oncology, Merck HealthCare KGaA
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Christopher Stroh
Translational Innovation Platform Oncology, Merck HealthCare KGaA
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Beat Bojaxhiu
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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Aurélie Quintin
Department for Biomedical Research, Inselspital, Bern University Hospital, and University of Bern
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Marco D Caversaccio
Universitätsklinik für HNO, Kopf- und Halschirurgie, Inselspital, Bern University Hospital, and University of Bern
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Matthias S. Dettmer
Institute of Pathology, University of Bern
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  • ORCID record for Matthias S. Dettmer
Mélanie Buchwalder
Universitätsklinik für HNO, Kopf- und Halschirurgie, Inselspital, Bern University Hospital, and University of Bern
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Tess M. Brodie
Mass Cytometry Facility, Univerity of Zurich
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Daniel M Aebersold
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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  • ORCID record for Daniel M Aebersold
Yitzhak Zimmer
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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Thomas E. Carey
Otolaryngology-Head and Neck Surgery, University of Michigan-Ann Arbor
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Michaela Medová
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern
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  • ORCID record for Michaela Medová
  • For correspondence: michaela.medova@dbmr.unibe.ch
DOI: 10.1158/1535-7163.MCT-18-1274
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Abstract

Radiotherapy (RT) is along with surgery the mainstay of treatment in head and neck squamous cell carcinoma (HNSCC). Radioresistance represents a major source of treatment failure, underlining the urgent necessity to explore and implement effective radiosensitization strategies. The MET receptor widely participates in acquisition and maintenance of an aggressive phenotype in HNSCC and modulates the DNA damage response following ionizing radiation (IR). Here we assessed MET expression and mutation status in primary and metastatic lesions within a cohort of patients with advanced HNSCC. Moreover, we investigated the radiosensitization potential of the MET inhibitor tepotinib in a panel of cell lines, in vitro and in vivo, as well as in ex vivo patient-derived organotypic tissue cultures (OTCs). MET was highly expressed in 62.4% of primary tumors and in 53.6% of lymph node metastases (LNMs), and in 6 out of 9 evaluated cell lines. MET expression in primaries and LNMs was significantly associated with decreased disease control in univariate survival analyses. Tepotinib abrogated MET phosphorylation and to distinct extents MET downstream signaling. Pretreatment with tepotinib resulted in variable radiosensitization, enhanced DNA damage, cell death, and G2/M-phase arrest. Combination of tepotinib with IR led to significant radiosensitization in one of two tested in vivo models. OTCs revealed differential patterns of response towards tepotinib, irradiation, and combination of both modalities. The molecular basis of tepotinib-mediated radiosensitization was studied by a CyTOF-based single-cell mass cytometry approach, which uncovered that MET inhibition modulated PI3K activity in cells radiosensitized by tepotinib but not in the resistant ones.

  • Received November 13, 2018.
  • Revision received August 19, 2019.
  • Accepted November 14, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst November 19, 2019
doi: 10.1158/1535-7163.MCT-18-1274

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Targeting the MET receptor tyrosine kinase as a strategy for radiosensitization in loco-regionally advanced head and neck squamous cell carcinoma
Lluís Nisa, Paola Francica, Roland Giger, Matúš Medo, Olgun Elicin, Manja Friese-Hamim, Claudia Wilm, Christopher Stroh, Beat Bojaxhiu, Aurélie Quintin, Marco D Caversaccio, Matthias S. Dettmer, Mélanie Buchwalder, Tess M. Brodie, Daniel M Aebersold, Yitzhak Zimmer, Thomas E. Carey and Michaela Medová
Mol Cancer Ther November 19 2019 DOI: 10.1158/1535-7163.MCT-18-1274

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Targeting the MET receptor tyrosine kinase as a strategy for radiosensitization in loco-regionally advanced head and neck squamous cell carcinoma
Lluís Nisa, Paola Francica, Roland Giger, Matúš Medo, Olgun Elicin, Manja Friese-Hamim, Claudia Wilm, Christopher Stroh, Beat Bojaxhiu, Aurélie Quintin, Marco D Caversaccio, Matthias S. Dettmer, Mélanie Buchwalder, Tess M. Brodie, Daniel M Aebersold, Yitzhak Zimmer, Thomas E. Carey and Michaela Medová
Mol Cancer Ther November 19 2019 DOI: 10.1158/1535-7163.MCT-18-1274
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Molecular Cancer Therapeutics
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