1. Academic Validation
  2. MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

  • Int J Cancer. 2019 Aug 1;145(3):748-762. doi: 10.1002/ijc.32170.
Ofra Novoplansky 1 2 Matthew Fury 3 Manu Prasad 1 2 Ksenia Yegodayev 1 2 Jonathan Zorea 1 2 Limor Cohen 1 2 Raphael Pelossof 4 Liz Cohen 1 2 Nora Katabi 5 Fabiola Cecchi 6 Ben-Zion Joshua 2 7 Aron Popovtzer 8 9 Jose Baselga 10 Maurizio Scaltriti 5 11 Moshe Elkabets 1 2
Affiliations

Affiliations

  • 1 The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 2 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 4 Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 5 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 6 NantOmics 9600 Medical Center Drive, Rockville, MD.
  • 7 Department of Otolaryngology - Head and Neck Surgery, Soroka University Medical Center, Beer-Sheva, Israel.
  • 8 Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
  • 9 The Head and Neck Cancer Radiation Clinic, Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel.
  • 10 Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 11 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
Abstract

An understanding of the mechanisms underlying acquired resistance to cetuximab is urgently needed to improve cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Here, we present a clinical observation that MET pathway activation constitutes the mechanism of acquired resistance to cetuximab in a patient with HNSCC. Specifically, RNA sequencing and mass spectrometry analysis of cetuximab-sensitive (CetuxSen ) and cetuximab-resistant (CetuxRes ) tumors indicated MET amplification and overexpression in the CetuxRes tumor compared to the CetuxSen lesion. Stimulation of MET in HNSCC cell lines was sufficient to reactivate the MAPK pathway and to confer resistance to cetuximab in vitro and in vivo. In addition to the direct role of MET in reactivation of the MAPK pathway, MET stimulation abrogates the well-known cetuximab-induced compensatory feedback loop of HER2/HER3 expression. Mechanistically, we showed that the overexpression of HER2 and HER3 following cetuximab treatment is mediated by the ETS homologous transcription factor (EHF), and is suppressed by MET/MAPK pathway activation. Collectively, our findings indicate that evaluation of MET and HER2/HER3 in response to cetuximab in HNSCC patients can provide the rationale of successive line of treatment.

Keywords

MET; cetuximab; drug resistance; head and neck cancer; signaling.

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