Patient-specific Boolean models of signaling networks guide personalized treatments

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. 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 personalized Boolean models and illustrate how they can be used for precision oncology.

Competing Interest Statement

LT is a full-time employee and shareholder of AstraZeneca. LP is a scientific advisor and RA is CEO of Astridbio Technologies Ltd. VS is a full-time employee of AstraZeneca. JSR receives funding from GSK and Sanofi and consultant fees from Travere Therapeutics. The other authors declare no conflicts of interest.

Footnotes

* https://github.com/ArnauMontagud/PROFILE_v2