Overcoming cetuximab resistance in HNSCC: the role of AURKB and DUSP proteins

Carolien Boeckx; Ken Op de Beeck; An Wouters; Vanessa Deschoolmeester; Ridha Limame; Karen Zwaenepoel; Pol Specenier; Patrick Pauwels; Jan B Vermorken; Marc Peeters; Guy Van Camp; Marc Baay; Filip Lardon

doi:10.1016/j.canlet.2014.08.039

Overcoming cetuximab resistance in HNSCC: the role of AURKB and DUSP proteins

Cancer Lett. 2014 Nov 28;354(2):365-77. doi: 10.1016/j.canlet.2014.08.039. Epub 2014 Sep 2.

Authors

Affiliations

¹ Center for Oncological Research (CORE) Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium. Electronic address: carolien.boeckx@uatnwerpen.be.
² Center for Oncological Research (CORE) Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium; Center for Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium; Antwerp University Hospital, Wilrijkstraat 10, Antwerpen, Belgium.
³ Center for Oncological Research (CORE) Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium.
⁴ Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, Antwerpen, Belgium.
⁵ Center for Oncological Research (CORE) Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium; Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, Antwerpen, Belgium.
⁶ Center for Oncological Research (CORE) Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium; Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, Antwerpen, Belgium.
⁷ Center for Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein1, Wilrijk, Belgium; Antwerp University Hospital, Wilrijkstraat 10, Antwerpen, Belgium.

PMID: 25192874
DOI: 10.1016/j.canlet.2014.08.039

Abstract

Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Our microarray results suggest that "resistant" cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC.

Keywords: Anti-EGFR therapy; Aurora kinase B; Cetuximab resistance; Dual-specificity phosphatase 5 and 6; Head and neck squamous cell carcinoma; NanoPro 1000.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal, Humanized / administration & dosage
Antibodies, Monoclonal, Humanized / pharmacology*
Antineoplastic Agents / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Aurora Kinase B / metabolism*
Carcinoma, Squamous Cell / drug therapy*
Carcinoma, Squamous Cell / enzymology*
Carcinoma, Squamous Cell / genetics
Cell Line, Tumor
Cetuximab
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Synergism
Dual-Specificity Phosphatases / metabolism*
Gene Expression Profiling
Head and Neck Neoplasms / drug therapy*
Head and Neck Neoplasms / enzymology*
Head and Neck Neoplasms / genetics
Humans
MAP Kinase Signaling System / drug effects
Male
Middle Aged
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 / metabolism
Organophosphates / administration & dosage
Organophosphates / pharmacology
Panitumumab
Phosphorylation
Quinazolines / administration & dosage
Quinazolines / pharmacology
Squamous Cell Carcinoma of Head and Neck

Substances

2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Organophosphates
Quinazolines
Panitumumab
AURKB protein, human
Aurora Kinase B
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Dual-Specificity Phosphatases
Cetuximab