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Medientyp:
E-Artikel
Titel:
An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer
Beteiligte:
van der Noord, Vera E.;
McLaughlin, Ronan P.;
Smid, Marcel;
Foekens, John A.;
Martens, John W. M.;
Zhang, Yinghui;
van de Water, Bob
Erschienen:
Springer Science and Business Media LLC, 2019
Erschienen in:
Scientific Reports, 9 (2019) 1
Sprache:
Englisch
DOI:
10.1038/s41598-019-49809-3
ISSN:
2045-2322
Entstehung:
Anmerkungen:
Beschreibung:
AbstractTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor clinical prognosis and limited targeted treatment strategies. Kinase inhibitor screening of a panel of 20 TNBC cell lines uncovered three critical TNBC subgroups: 1) sensitive to only MEK inhibitors; 2) sensitive to only Akt inhibitors; 3) resistant to both MEK/Akt inhibitors. Using genomic, transcriptomic and proteomic datasets of these TNBC cell lines we unravelled molecular features associated with the MEK and Akt drug resistance. MEK inhibitor-resistant TNBC cell lines were discriminated from Akt inhibitor-resistant lines by the presence of PIK3CA/PIK3R1/PTEN mutations, high p-Akt and low p-MEK levels, yet these features could not distinguish double-resistant cells. Gene set enrichment analyses of transcriptomic and proteomic data of the MEK and Akt inhibitor response groups revealed a set of cell cycle-related genes associated with the double-resistant phenotype; these genes were overexpressed in a subset of breast cancer patients. CDK inhibitors targeting the cell cycle programme could overcome the Akt and MEK inhibitor double-resistance. In conclusion, we uncovered molecular features and alternative treatment strategies for TNBC that are double-resistant to Akt and MEK inhibitors.