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

Ofra Novoplansky; Matthew Fury; Manu Prasad; Ksenia Yegodayev; Jonathan Zorea; Limor Cohen; Raphael Pelossof; Liz Cohen; Nora Katabi; Fabiola Cecchi; Ben-Zion Joshua; Aron Popovtzer; Jose Baselga; Maurizio Scaltriti; Moshe Elkabets

doi:10.1002/ijc.32170

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. Epub 2019 Feb 11.

Authors

Ofra Novoplansky^{1

2}, Matthew Fury³, Manu Prasad^{1

2}, Ksenia Yegodayev^{1

2}, Jonathan Zorea^{1

2}, Limor Cohen^{1

2}, Raphael Pelossof⁴, Liz Cohen^{1

2}, Nora Katabi⁵, Fabiola Cecchi⁶, Ben-Zion Joshua^{2

7}, Aron Popovtzer^{8

9}, Jose Baselga¹⁰, Maurizio Scaltriti^{5

11}, Moshe Elkabets^{1

2}

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 (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.

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

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line, Tumor
Cetuximab / pharmacokinetics
Cetuximab / pharmacology*
Drug Resistance, Neoplasm
Enzyme Activation
Gene Expression
Head and Neck Neoplasms / drug therapy*
Head and Neck Neoplasms / enzymology
Head and Neck Neoplasms / genetics
Humans
Indoles / pharmacology
MAP Kinase Signaling System
Mice
Mice, Inbred NOD
Mice, SCID
Proto-Oncogene Proteins c-met / metabolism*
Random Allocation
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / biosynthesis
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism*
Receptor, ErbB-3 / antagonists & inhibitors
Receptor, ErbB-3 / biosynthesis
Receptor, ErbB-3 / genetics
Receptor, ErbB-3 / metabolism*
Squamous Cell Carcinoma of Head and Neck / drug therapy*
Squamous Cell Carcinoma of Head and Neck / enzymology
Squamous Cell Carcinoma of Head and Neck / genetics
Sulfones / pharmacology
Up-Regulation
Xenograft Model Antitumor Assays

Substances

5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
Indoles
Sulfones
ERBB2 protein, human
ERBB3 protein, human
MET protein, human
Proto-Oncogene Proteins c-met
Receptor, ErbB-2
Receptor, ErbB-3
Cetuximab

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States