An increased cell cycle gene network determines MEK and Akt inhibitor double resistance in triple-negative breast cancer
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Updated: Jan 19, 2026
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Published on: March 20, 2020
Vera E van der Noord1, Ronan P McLaughlin1, Marcel Smid2
1Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, PO box 9502, 2300, RA, Leiden, The Netherlands.
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.
Insights
Triple-negative breast cancer (TNBC) exhibits distinct subgroups based on MEK and Akt inhibitor sensitivity. Targeting cell cycle pathways with CDK inhibitors offers a new strategy for drug-resistant TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies.
- Kinase inhibitors targeting MEK and Akt pathways are potential treatments for TNBC.
- Understanding drug resistance mechanisms is crucial for improving TNBC treatment outcomes.
Purpose of the Study:
- To identify molecular features associated with MEK and Akt inhibitor resistance in TNBC.
- To explore alternative therapeutic strategies for TNBC resistant to both MEK and Akt inhibitors.
- To investigate the role of cell cycle genes in TNBC drug resistance.
Main Methods:
- Screening of 20 TNBC cell lines with kinase inhibitors.
- Genomic, transcriptomic, and proteomic data analysis.
- Gene set enrichment analysis to identify molecular pathways.
- Evaluation of CDK inhibitors for overcoming drug resistance.
Main Results:
- Three TNBC subgroups were identified: MEK inhibitor-sensitive, Akt inhibitor-sensitive, and double-resistant.
- PIK3CA/PIK3R1/PTEN mutations, high p-Akt, and low p-MEK levels characterized MEK inhibitor resistance.
- Cell cycle-related genes were overexpressed in double-resistant TNBC and associated with poor prognosis.
- CDK inhibitors demonstrated efficacy in overcoming dual MEK/Akt inhibitor resistance.
Conclusions:
- Distinct molecular profiles differentiate TNBC subgroups based on MEK and Akt inhibitor response.
- Cell cycle dysregulation is a key mechanism in dual MEK/Akt inhibitor-resistant TNBC.
- CDK inhibitors represent a promising therapeutic avenue for overcoming TNBC drug resistance.
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