Fig. 2: The experimentally-measured response to BH3-mimetics can be predicted by simulating a heterogeneous population of RC-K8 cells.

A Comparison of the relative protein expression in the computational model to experimental data. Abundance of each protein is normalized to the most highly expressed anti-apoptotic BCL2 family protein and quantified from ref. ¹³. B Comparison of the proportion of pro-apoptotic and BH3-only BCL2 proteins bound to BCL-xL in the computational simulation compared to experimental data quantified from ref. ¹³. C Schematic of the method used to simulate BCL-xL inhibition in a heterogeneous cell population. From the RC-K8-speific parameterization established in panels A and B initial conditions are independently sampled from a log-normal distribution to create heterogeneous cells with distinct starting states. Within all cells in the population the target protein (e.g., BCL-xL) is inhibited and the response to this perturbation recorded (see Methods). D Line graphs showing the simulated response to 50% BCL-xL inhibition in a heterogeneous RC-K8 cell population. A threshold of death (10% higher than is present within the naive population) is calculated. The time of death of in each cell is determined as the time this threshold is crossed (top panel). The percentage viability of the cell population can then be determined over time in response to BCL-xL inhibition (bottom panel). E Schematic showing that the process used to simulate BCL-xL inhibition in A to D is repeated for multiple BH3-mimetics. F Line graph of the simulated viability of the RC-K8 cell population in response to BCL2 inhibition (black), BCL-xL inhibition (red) and MCL1 inhibition (blue). The viability of the cell population is recorded to 72 h to match experimental methods. G Schematic showing that the process used to simulate 50% inhibition in panels A to F is repeated for 10 distinct strengths of inhibition between 0 and 100% to enable comparison to dose-response experiments. H Line graphs showing the simulated percentage of the RC-K8 cell population viable at each percentage inhibition of the indicated target protein. This prediction can be compared to experimentally measured EC₅₀ values, right¹³.