title: Transcriptional upregulation of HER2 expression in the absence of HER2             gene amplification results in cetuximab resistance that is reversed by trastuzumab             treatment.
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.
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliveras-Ferraros
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer Vall-Llovera
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.forename: Dolors Carrion
authors.initials: DC
authors.lastname: Salip
authors.forename: Bernardo
authors.initials: B
authors.lastname: Queralt
authors.forename: Silvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Rafael
authors.initials: R
authors.lastname: De Llorens
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D000068878:Trastuzumab; D015854:Up-Regulation; D018631:ras Proteins / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D000077341:Lapatinib; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D018631:ras Proteins; C117307:KRAS protein, human; C508053:ERBB2 protein, human