Abstract | PURPOSE:
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. EXPERIMENTAL DESIGN: 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.
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Authors | T Rampias, A Giagini, S Siolos, H Matsuzaki, C Sasaki, A Scorilas, A Psyrri |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 20
Issue 11
Pg. 2933-46
(Jun 01 2014)
ISSN: 1557-3265 [Electronic] United States |
PMID | 24696319
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Phosphatidylinositol 3-Kinases
- ras Proteins
- Cetuximab
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Topics |
- Animals
- Antibodies, Monoclonal, Humanized
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Blotting, Western
- Carcinoma, Squamous Cell
(genetics, metabolism)
- Cetuximab
- Drug Resistance, Neoplasm
(genetics)
- Gene Knock-In Techniques
- Head and Neck Neoplasms
(genetics, metabolism)
- Humans
- MAP Kinase Signaling System
(physiology)
- Mice
- Mice, Transgenic
- Microscopy, Confocal
- Mutation
- Phosphatidylinositol 3-Kinases
(metabolism)
- Real-Time Polymerase Chain Reaction
- Receptor Cross-Talk
(physiology)
- Reverse Transcriptase Polymerase Chain Reaction
- Squamous Cell Carcinoma of Head and Neck
- Transcriptome
- ras Proteins
(genetics, metabolism)
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