Peer Reviewed

1

Document Type

Article

Publication Date

19-1-2018

Keywords

Systems Biology, TNBC, BCL2 proteins, Cell Death, Predictive model

Funder/Sponsor

Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT

Comments

This article is also available at https://www.nature.com/articles/s41419-017-0039-y

Abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer which accounts for 15-20% of this disease and is currently treated with genotoxic chemotherapy. The BCL2 (B-cell lymphoma 2) family of proteins controls the process of mitochondrial outer membrane permeabilization (MOMP), which is required for the activation of the mitochondrial apoptosis pathway in response to genotoxic agents. We previously developed a deterministic systems model of BCL2 protein interactions, DR_MOMP that calculates the sensitivity of cells to undergo mitochondrial apoptosis. Here we determined whether DR_MOMP predicts responses of TNBC cells to genotoxic agents and the re-sensitization of resistant cells by BCL2 inhibitors. Using absolute protein levels of BAX, BAK, BCL2, BCL(X)L and MCL1 as input for DR_MOMP, we found a strong correlation between model predictions and responses of a panel of TNBC cells to 24 and 48 h cisplatin (R2 = 0.96 and 0.95, respectively) and paclitaxel treatments (R2 = 0.94 and 0.95, respectively). This outperformed single protein correlations (best performer BCL(X)L with R2 of 0.69 and 0.50 for cisplatin and paclitaxel treatments, respectively) and BCL2 proteins ratio (R2 of 0.50 for cisplatin and 0.49 for paclitaxel). Next we performed synergy studies using the BCL2 selective antagonist Venetoclax /ABT199, the BCL(X)L selective antagonist WEHI-539, or the MCL1 selective antagonist A-1210477 in combination with cisplatin. In silico predictions by DR_MOMP revealed substantial differences in treatment responses of BCL(X)L, BCL2 or MCL1 inhibitors combinations with cisplatin that were successfully validated in cell lines. Our findings provide evidence that DR_MOMP predicts responses of TNBC cells to genotoxic therapy, and can aid in the choice of the optimal BCL2 protein antagonist for combination treatments of resistant cells.

Disciplines

Cancer Biology | Cell Biology | Physiology | Systems Biology

Citation

Lucantoni F, Lindner AU, O'Donovan N, Dussmann H, Prehn JHM. Systems modeling accurately predicts responses to genotoxic agents and their synergism with BCL-2 inhibitors in triple negative breast cancer cells. Cell Death and Disease. 2018; 9(2):42

PubMed ID

29352235

DOI Link

10.1038/s41419-017-0039-y

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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