Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma

Abstract

The heterogeneous polyclonal nature of multiple myeloma complicates the identification of protein biomarkers predictive of drug response. In this study, a pharmacodynamic systems modeling approach was used to link in vitro bortezomib exposure and myeloma cell death. The exposure‐response was integrated through a network of important protein biomarker dynamics activated by bortezomib in four myeloma cell lines. The pharmacodynamic models reasonably characterized the protein and myeloma cell dynamics simultaneously following bortezomib (20 nM) treatment. The models were used to identify differences in pathway dynamics across cell lines from model‐estimated protein biomarker turnover parameters and global sensitivity analyses. Additionally, a statistical correlation analysis between drug sensitivity and model‐fitted protein activation profiles (i.e., cumulative area under the protein expression‐time curves) supported the identification of shared biomarkers associated with sensitivity differences among the cell lines. Both types of analysis identified similar important proteins associated with bortezomib pharmacodynamics, such as phosphorylated Nuclear Factor kappa‐light‐chain‐enhancer of activated B cells (pNFkappaB), phosphorylated protein kinase B (pAKT), and caspase‐8 (Cas 8).