Abstract P1-02-06: Computational modeling predicts drugs response to targeting metabolism in breast cancer cells

Abstract

Abstract Background Reprogramming of metabolism is a hallmark in cancer. In previous works we observed differences in glucose metabolism between tumors from different breast cancer subtypes, suggesting the possibility to use drugs against metabolism in this disease. Flux Balance Analysis (FBA) is widely used to study biochemical networks, allowing to predict growth rates and to simulate drug response. Material and methods Breast cancer cell lines and different drugs against metabolic targets were evaluated with dose-response curves, and pharmacological parameters for each condition were calculated. Proteomics data from breast cancer cells lines treated with sub-lethal doses and controls were obtained applying a mass spectrometry-based approach. Differences in protein expression between treated vs. control were assessed. An FBA approach using the human metabolic reconstruction Recon2 and including the protein expression values from perturbation experiments was also applied. Model predictions were validated using dynamic FBA and growth rate for each sample was estimated. With the aim to compare the activity of the different pathway fluxes between control and treated cells, flux activity was calculated for each condition and for each pathway and response predictive models were performed. Results Drug response was diverse across different breast cancer cells. Mass spectrometry from cell samples allows identifying and quantifying 4,114 proteins. FBA predicted that growth rates decrease in treated cells vs. control, as observed in cell viability assays. Dynamic FBA showed that our model correctly reflects cell growth rates. Finally, using flux activities, it is possible to build models which could predict response against these drugs. Conclusions Proteomics provide insights of the mechanisms responsible of cells' response to metabolism drugs. A validated computational model able to predict tumor growth using data from proteomics was developed. Model predicts growth rates and also dysregulation of biological processes triggered by drug treatment. Moreover, these computational approaches could be used to propose new mechanisms of action and effects of metabolic drugs. Acknowledgments This work was supported by grant PI15/01310 from Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry, Spain and co-funded by FEDER program, “Una forma de hacer Europa”. L.T.-F is supported by Spanish Economy and Competitiveness Ministry grant DI-15-07614. Competing interest JAFV, AG-P and EE are stakeholders of Biomedica Molecular Medicine S.L. and Biomedica Molecular Medicine Ltd. LT-F is an employee of Biomedica Molecular Medicine S.L. The authors have declared no other conflict of interest. Citation Format: Zamora Auñón P, Trilla-Fuertes L, Díaz-Almirón M, Gamez-Pozo A, Prado-Vázquez G, Zapater-Moros A, Llorente-Armijo S, Gaya Romero F, Espinosa Arranz E, Fresno-Vara JA. Computational modeling predicts drugs response to targeting metabolism in breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-06.