In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-09-16)
Abstract:
Triple-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.
Type of Medium:
Online Resource
ISSN:
2045-2322
DOI:
10.1038/s41598-019-49809-3
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2615211-3
