Fig 2: Simulated protein expression levels at t = 72 hour in comparison to experimentally-measured protein expression in MOLM-13 R2 cells.Blue circles correspond to the average of experimental measurements and error bars correspond to one standard deviation. Plots illustrate total protein expression levels for Mcl-1, Bcl-2, Bim, Bax, Bak, c-Myc, and Chop, and active Caspase-3 levels only. All protein levels are normalized to the expression in the untreated system. (a) 400 nM venetoclax monotherapy, (b) 5,000 nM tedizolid monotherapy, (c) 400 nM venetoclax and 5,000 nM tedizolid combination therapy administered simultaneously. (d) Shows the predicted c-Myc-dependent regulatory functions for each Bcl-2 family protein in the model, normalized by the transcription factor-dependent maximal production rate for each protein. The boundaries separating distinct zones are illustrative and were chosen as approximately the concentration of c-Myc that separates states where pro-apoptotic c-Myc-dependent regulatory functions are predominantly saturated from states where the anti-apoptotic c-Myc-dependent regulatory functions are predominantly saturated (see Eqs. (A.18)-(A.22) in S1 Text).

Fig 3: Results of local sensitivity analysis around the nominal parameter set for (a) the untreated system, (b) 400 nM venetoclax monotherapy, (c) 5,000 nM tedizolid monotherapy, and (d) 400 nM venetoclax and 5,000 nM tedizolid combination therapy. Plots show the relative sensitivity calculated using Eq (2) resulting from perturbations of ±1% to individual kinetic parameters or initial conditions in each treatment case. Top 20 kinetic parameters/initial conditions are shown in each plot. Asterisks denote kinetic parameters that affect the expression of the transcription factors c-Myc and Chop (see Ref. [116]).

Fig 4: Results of pre-treatment before the administration of 400 nM venetoclax and 5,000 nM tedizolid combination therapy.(a) Simulated response values, calculated using Eq (3), for 400 nM venetoclax administered prior to combination therapy and for 5,000 nM tedizolid administered prior to combination therapy, with the indicated pre-treatment windows. Combination therapy was simulated for 5 days following pre-treatment. (b) Simulated peak and end-point live cell counts during the combination therapy with different pre-treatment windows. In (a) and (b), a pre-treatment window of “0” corresponds to combination therapy without pre-treatment. (c) Simulated expression of Chop, free (inactive) Bak, and free Mcl-1 protein levels after the administration of 5,000 nM tedizolid monotherapy. Each protein was normalized to its total expression in the untreated system. (d) Active Caspase-3 levels, normalized to the level in the untreated system, observed in simulations of combination therapy without pre-treatment and with tedizolid administered 36 hours prior to combination therapy. Time is measured relative to the administration of venetoclax. (e) Experimentally-measured cellular viability for MOLM-13 R2 cells treated with venetoclax monotherapy, combination venetoclax/tedizolid therapy without pre-treatment, or combination therapy with tedizolid pre-treatment administered 48 hours prior, at the indicated venetoclax concentrations. Cellular viability was measured 72 hours after the administration of venetoclax and has been normalized to the cellular viability in the untreated cells. Data points show average and standard deviation of experimental measurements, and solid lines correspond to sigmoidal fits to the data (see text for further details).