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MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer
Author(s) -
Novoplansky Ofra,
Fury Matthew,
Prasad Manu,
Yegodayev Ksenia,
Zorea Jonathan,
Cohen Limor,
Pelossof Raphael,
Cohen Liz,
Katabi Nora,
Cecchi Fabiola,
Joshua BenZion,
Popovtzer Aron,
Baselga Jose,
Scaltriti Maurizio,
Elkabets Moshe
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32170
Subject(s) - cetuximab , head and neck squamous cell carcinoma , cancer research , mapk/erk pathway , medicine , downregulation and upregulation , head and neck cancer , cancer , colorectal cancer , oncology , signal transduction , biology , biochemistry , gene
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 (Cetux Sen ) and cetuximab‐resistant (Cetux Res ) tumors indicated MET amplification and overexpression in the Cetux Res tumor compared to the Cetux Sen 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.