Data-Driven Modeling of Src Control on the Mitochondrial Pathway of Apoptosis: Implication for Anticancer Therapy Optimization

Src tyrosine kinases are deregulated in numerous cancers and may favor tumorigenesis and tumor progression. We previously described that Src activation in NIH-3T3 mouse fibroblasts promoted cell resistance to apoptosis. Indeed, Src was found to accelerate the degradation of the pro-apoptotic BH3-only protein Bik and compromised Bax activation as well as subsequent mitochondrial outer membrane permeabilization. The present study undertook a systems biomedicine approach to design optimal anticancer therapeutic strategies using Src-transformed and parental fibroblasts as a biological model. First, a mathematical model of Bik kinetics was designed and fitted to biological data. It guided further experimental investigation that showed that Bik total amount remained constant during staurosporine exposure, and suggested that Bik protein might undergo activation to induce apoptosis. Then, a mathematical model of the mitochondrial pathway of apoptosis was designed and fitted to experimental results. It showed that Src inhibitors could circumvent resistance to apoptosis in Src-transformed cells but gave no specific advantage to parental cells. In addition, it predicted that inhibitors of Bcl-2 antiapoptotic proteins such as ABT-737 should not be used in this biological system in which apoptosis resistance relied on the deficiency of an apoptosis accelerator but not on the overexpression of an apoptosis inhibitor, which was experimentally verified. Finally, we designed theoretically optimal therapeutic strategies using the data-calibrated model. All of them relied on the observed Bax overexpression in Src-transformed cells compared to parental fibroblasts. Indeed, they all involved Bax downregulation such that Bax levels would still be high enough to induce apoptosis in Src-transformed cells but not in parental ones. Efficacy of this counterintuitive therapeutic strategy was further experimentally validated. Thus, the use of Bax inhibitors might be an unexpected way to specifically target cancer cells with deregulated Src tyrosine kinase activity.