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bioRxiv · 10.1101/128801

An Integrated Mechanistic Model of Pan-Cancer Driver Pathways Predicts Stochastic Proliferation and Death

Bouhaddou, M.·Barrette, A. M.·Koch, R. J.·DiStefano, M. S.·Riesel, E. A.·Stern, A. D.·Santos, L. C.·Tan, A.·Mertz, A.·Birtwistle, M. R.
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Abstract

Most cancer cells harbor multiple drivers whose epistasis and interactions with expression context clouds drug sensitivity prediction. We constructed a mechanistic computational model that is context-tailored by omics data to capture regulation of stochastic proliferation and death by pan-cancer driver pathways. Simulations and experiments explore how the coordinated dynamics of RAF/MEK/ERK and PI-3K/AKT kinase activities in response to synergistic mitogen or drug combinations control cell fate in a specific cellular context. In this context, synergistic ERK and AKT inhibitor-induced death is likely mediated by BIM rather than BAD. AKT dynamics explain S-phase entry synergy between EGF and insulin, but stochastic ERK dynamics seem to drive cell-to-cell proliferation variability, which in simulations are predictable from pre-stimulus fluctuations in C-Raf/B-Raf levels. Simulations predict MEK alteration negligibly influences transformation, consistent with clinical data. Our model mechanistically interprets context-specific landscapes between driver pathways and cell fates, moving towards more rational cancer combination therapy.

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Bouhaddou, M., Barrette, A. M., Koch, R. J., DiStefano, M. S., Riesel, E. A., Stern, A. D., Santos, L. C., Tan, A., Mertz, A., Birtwistle, M. R.. 2017-04-19. An Integrated Mechanistic Model of Pan-Cancer Driver Pathways Predicts Stochastic Proliferation and Death. https://doi.org/10.1101/128801

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