Patient-specific Boolean models of signalling networks guide personalised treatments.

Arnau Montagud,Róbert Alföldi,Jonas Béal,Vigneshwari Subramanian,Bence Szalai,Julio Saez-Rodriguez,Emmanuel Barillot,Pauline Traynard,Laurence Calzone,Luis Tobalina,Alfonso Valencia,László Puskás

doi:10.7554/elife.72626

Abstract

Prostate cancer is the second most occurring cancer in men worldwide. To better understand the mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model of prostate cancer which considers the major signalling pathways known to be deregulated. We personalised this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients. A total of 488 prostate samples were used to build patient-specific models and compared to available clinical data. Additionally, eight prostate cell line-specific models were built to validate our approach with dose-response data of several drugs. The effects of single and combined drugs were tested in these models under different growth conditions. We identified 15 actionable points of interventions in one cell line-specific model whose inactivation hinders tumorigenesis. To validate these results, we tested nine small molecule inhibitors of five of those putative targets and found a dose-dependent effect on four of them, notably those targeting HSP90 and PI3K. These results highlight the predictive power of our personalised Boolean models and illustrate how they can be used for precision oncology.

Highlights

Like most cancers, prostate cancer arises from mutations in single somatic cells that induce deregulations in processes such as proliferation, invasion of adjacent tissues and metastasis
To identify drugs that could act as potential inhibitors of the genes identified with the Boolean model, we explored the drug-target associations in DrugBank (Wishart et al, 2018) and ChEMBL (Gaulton et al, 2017)
Clinical assessment of cancers is moving towards more precise, personalised treatments, as the times of one-size-fits-all treatments are no longer appropriate, and patient-tailored models could boost the success rate of these treatments in clinical practice

Summary

Introduction

Prostate cancer arises from mutations in single somatic cells that induce deregulations in processes such as proliferation, invasion of adjacent tissues and metastasis. The high heterogeneity of these profiles can be explained by a large number of interacting proteins and the complex crosstalks between the cell signalling pathways that can be altered in cancer cells. Because of this complexity, understanding the process of tumorigenesis and tumour growth would benefit from a systemic and dynamical description of the disease. Boolean models, the simplest implementation of logical models, describe each protein as a binary variable (ON/OFF) This framework is flexible, requires in principle no quantitative information, can be applied to large networks combining multiple pathways, and can provide a qualitative understanding of molecular systems lacking detailed mechanistic information

Methods

Results

Conclusion