RAS/PI3K crosstalk and cetuximab resistance in head and neck squamous cell carcinoma.
OBJECTIVE
Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism.


METHODS
To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. We also used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance.


RESULTS
Here, we show that activation of RAS signaling leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy.


CONCLUSIONS
Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature. Clin Cancer Res; 20(11); 2933-46. ©2014 AACR.
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Rampias
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Giagini
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Siolos
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Matsuzaki
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Sasaki
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Scorilas
Authors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, GreeceAuthors' Affiliations: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Attikon Hospital; and Department of Biochemistry and Molecular Biology, Faculty of Biology, National Kapodistrian University of Athens, University of Athens, Greece.
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Psyrri
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055879:Gene Knock-In Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D059467:Transcriptome; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins; D000068818:Cetuximab