101. Transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification results in cetuximab resistance that is reversed by trastuzumab treatment.
- Author
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Oliveras-Ferraros C, Massaguer Vall-Llovera A, Vazquez-Martin A, Salip DC, Queralt B, Cufí S, Martin-Castillo B, Bosch-Barrera J, Brunet J, De Llorens R, and Menendez JA
- Subjects
- Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Carcinoma, Squamous Cell immunology, Carcinoma, Squamous Cell metabolism, Cell Survival drug effects, Cetuximab, Drug Resistance, Neoplasm genetics, Gene Amplification, Humans, Lapatinib, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins p21(ras), Quinazolines pharmacology, Receptor, ErbB-2 biosynthesis, Transcription, Genetic, Trastuzumab, Up-Regulation, ras Proteins biosynthesis, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Receptor, ErbB-2 genetics
- Abstract
The recent identification of HER2 gene amplification as a novel predictor of resistance to the EGFR (HER2)-targeted antibody cetuximab and of response to combination therapies against EGFR and HER2 in wild-type KRAS tumor settings may represent a further step toward personalized medicine for patients with colorectal cancer. Herein, we show that transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification is a molecular phenomenon that takes place in EGFR-dependent, wild-type KRAS squamous cell carcinoma (SCC) cells that acquire resistance to cetuximab. Since cetuximab activity against cetuximab-refractory SCC cells can be fully restored in the presence of the anti-HER2 monoclonal antibody trastuzumab, our findings suggest that, beyond HER2 gene amplification, we might need to redefine the threshold values for HER2 positivity to improve the accuracy of the selection of cetuximab-refractory patients with wild-type KRAS that may benefit from receiving a cetuximab/trastuzumab combination.
- Published
- 2012
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