Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab

ABSTRACT: HCC827 cells were grown in gradually increasing concentrations of cetuximab beginning at 0.1 ug/ml. Drug concentrations were slowly increased until the resistant cells were able to proliferate in 100 ug/ml of cetuximab. Individual clones of cetuximab resistant (CR; CR1 to CR4) cells were isolated and confirmed to be drug resistant. Number of samples: 5. Parental HCC827 as a control. 4 Cetuximab resistant clones

ORGANISM(S): Homo sapiens

SUBMITTER: Pasi Jänne

PROVIDER: E-GEOD-30255 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.

Yonesaka Kimio K Zejnullahu Kreshnik K Okamoto Isamu I Satoh Taroh T Cappuzzo Federico F Souglakos John J Ercan Dalia D Rogers Andrew A Roncalli Massimo M Takeda Masayuki M Fujisaka Yasuhito Y Philips Juliet J Shimizu Toshio T Maenishi Osamu O Cho Yonggon Y Sun Jason J Destro Annarita A Taira Koichi K Takeda Koji K Okabe Takafumi T Swanson Jeffrey J Itoh Hiroyuki H Takada Minoru M Lifshits Eugene E Okuno Kiyotaka K Engelman Jeffrey A JA Shivdasani Ramesh A RA Nishio Kazuto K Fukuoka Masahiro M Varella-Garcia Marileila M Nakagawa Kazuhiko K Jänne Pasi A PA

Science translational medicine 20110901 99

Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or throug ...[more]

PMID: 21900593

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Project description:EGFR tyrosine kinase inhibitors (TKIs) have demonstrated tremendous clinical benefits in non-small cell lung cancer (NSCLC) patients. However, resistance emerges rapidly due to a variety of mechanisms including a secondary mutation of T790M in EGFR that abrogates the binding of the drugs. It has been postulated that EGFR TKIs, such as afatinib (BIBW2992), with activity against the T790M mutant EGFR kinase might overcome the drug resistance problem or, when used as the first-line treatment, delay or suppress the emergence of resistance in EGFR. In this study, we generated BIBW2992-resistant cells, HCC827-BR1 and HCC827-BR2, from the parental HCC827 cells. In HCC827-BR cells, EGFR, MET, and Erb2 were down-regulated and no secondary mutation was found to be present in the coding region of EGFR. Gene set enrichment analysis (GSEA) revealed an obvious signature of epithelial to mesenchymal transition (EMT) in the drug resistant cells. Subsequently, the HCC827-BR cells were shown to be more invasive. Most importantly, we strived to seek if alternative medicine might be applied alone or in combination to treat the BIBW2992-resistant cells or to, under BIBW2992 treatment, diminish the emergence of resistant cells. Compared to the parental cells, the HCC827-BR cells were more sensitive to dasatinib, an FDA-approved kinase inhibitor. Furthermore, as revealed in the clonogenicity assay, the reduction of tumor-colony-forming cells after exposure to BIBW2992 was substantially potentiated by low concentration of dasatinib. Thus, prospective clinical investigations may be needed to evaluate if dasatinib can be beneficial to patients receiving second-generation EGFR TKIs for the treatment of NSCLC. Over a period of 3-4 months, BIBW2992-resistant cells were isolated in cell culture by maintenance of HCC827 cells in the presence of escalating concentrations of BIBW2992 up to 2 Î¼M. Two cell lines, HCC827-BR1 and HCC827-BR2, were established based on individual clones. Total RNA of these HCC827, HCC827-BR1 and HCC827-BR2, were extracted for gene expression microarray analysis using Illumina HumanHT12 v3 BeadChip.

Dataset Information

Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab

Publications

Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.

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