Quantitative systems pharmacology modeling of tumor heterogeneity in response to BH3-mimetics using virtual tumors calibrated with cell viability assays
Intra-tumoral cell heterogeneity contributes to both primary and acquired resistance mechanisms, limiting the effectiveness of BH3-mimetics in inducing tumor cell apoptosis. This article introduces a novel quantitative systems pharmacology (QSP)-based approach that utilizes cell viability assays to calibrate virtual tumors (VTs) composed of virtual cells. Each cell’s fate is simulated using an apoptosis QSP model. VTs modeled on the SU-DHL-4 and KARPAS-422 cell lines were calibrated with in vitro data from venetoclax (targeting BCL2), A-1155463 (targeting BCLXL), and A-1210477 (targeting MCL1). These calibrated VTs offer insights into BH3-mimetic combinations by differentiating cells eliminated by individual drugs (monotherapies) from those requiring a combination therapy for effective elimination. Additionally, calibrated VTs serve as starting points in an agent-based model (ABM) framework; a minimal ABM was developed to link in vitro SU-DHL-4 cell viability results to tumor growth inhibition studies in mice.