Skip to content

Research at St Andrews

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

Research output: Contribution to journalArticle

Author(s)

Alexey Goltsov, Ghassan Tashkandi, Simon P. Langdon, David J. Harrison, James L. Bown

School/Research organisations

Abstract

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.
Close

Details

Original languageEnglish
Pages (from-to)170-181
JournalEuropean Journal of Pharmaceutical Sciences
Volume97
Early online date8 Nov 2016
DOIs
Publication statusPublished - 15 Jan 2017

    Research areas

  • Kinetic modelling, PI3K, mTOR1, PTEN, Rapamycin, BEZ235

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. The landscape of genomic copy number alterations in colorectal cancer and their consequences on gene expression levels and disease outcome

    Ried, T., Meijer, G. A., Harrison, D. J., Grech, G., Franch-Expósito, S., Briffa, R., Carvalho, B. & Camps, J., Oct 2019, In : Molecular Aspects of Medicine. 69, p. 48-61 14 p.

    Research output: Contribution to journalArticle

  2. Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

    Sarr, A., Bré, J., Um, I. H., Chan, T. H., Mullen, P., Harrison, D. J. & Reynolds, P. A., 21 May 2019, In : Scientific Reports. 9, 13 p., 7643.

    Research output: Contribution to journalArticle

  3. Raman spectroscopy investigation of biochemical changes in tumor spheroids with aging and after treatment with staurosporine

    Jamieson, L. E., Harrison, D. J. & Campbell, C. J., May 2019, In : Journal of Biophotonics. 12, 5, e201800201.

    Research output: Contribution to journalArticle

Related by journal

  1. Model-based global sensitivity analysis as applied to identification of anti-cancer drug targets and biomarkers of drug resistance in the ErbB2/3 network

    Lebedeva, G., Sorokin, A., Faratian, D., Mullen, P., Goltsov, A., Langdon, S. P., Harrison, D. J. & Goryanin, I., 16 Jul 2012, In : European Journal of Pharmaceutical Sciences. 46, 4, p. 244-258

    Research output: Contribution to journalArticle

ID: 247491280

Top