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An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer
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An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer
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Journal Article
An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer
2019
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/39
/ 38/61
/ 38/91
/ 82/1
/ 82/58
/ 82/80
/ Cell Proliferation - drug effects
/ Class I Phosphatidylinositol 3-Kinases - genetics
/ Class Ia Phosphatidylinositol 3-Kinase - genetics
/ Drug Resistance, Neoplasm - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Drug Resistance, Neoplasm - physiology
/ Female
/ Genes
/ Humanities and Social Sciences
/ Humans
/ MAP Kinase Kinase 1 - antagonists & inhibitors
/ MAP Kinase Kinase 1 - metabolism
/ Protein Kinase Inhibitors - pharmacology
/ Proto-Oncogene Proteins c-akt - antagonists & inhibitors
/ Proto-Oncogene Proteins c-akt - metabolism
/ PTEN Phosphohydrolase - genetics
/ Science
/ Signal Transduction - drug effects
/ Triple Negative Breast Neoplasms - drug therapy
