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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2013

AutorInnen: Li, J; Bennett, K; Stukalov, A; Fang, B; Zhang, G; Yoshida, T; Okamoto, I; Kim, JY; Song, L; Bai, Y; Qian, X; Rawal, B; Schell, M; Grebien, F; Winter, G; Rix, U; Eschrich, S; Colinge, J; Koomen, J; Superti-Furga, G; Haura, EB

Titel: Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.

Quelle: Mol Syst Biol. 2013; 9:705



Autor/innen der Vetmeduni Vienna:

Grebien Florian

Diese Publikation wurde nicht im Namen der Vetmeduni Vienna erstellt und ist deshalb ausschließlich der persönlichen Publikationsliste des/der Autors/Autorin zugeordnet!


Abstract:
We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein-protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems-level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14-protein core network critical to the viability of multiple EGFR-mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR-mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance.

Keywords Pubmed: Antineoplastic Agents/pharmacology
Carbazoles/pharmacology
Cell Line, Tumor
Cell Survival/drug effects
Drug Resistance, Neoplasm/drug effects
Drug Resistance, Neoplasm/genetics*
Drug Synergism
Erlotinib Hydrochloride
Gene Expression Regulation, Neoplastic*
Humans
Mutation*
Neoplasm Proteins/genetics
Neoplasm Proteins/metabolism*
Phosphorylation
Protein Interaction Maps
Protein Kinase Inhibitors/pharmacology
Quinazolines/pharmacology
Receptor, Epidermal Growth Factor/antagonists & inhibitors
Receptor, Epidermal Growth Factor/genetics
Receptor, Epidermal Growth Factor/metabolism*
Staurosporine/analogs & derivatives
Staurosporine/pharmacology


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