A quantitative systems pharmacological approach identified activation of JNK signaling pathway as a promising treatment strategy for refractory HER2 positive breast cancer

AbstractHER2-positive breast cancer (BC) is a rapidly growing and aggressive  BC subtype that predominantly affects younger women. Despite improvements in patient outcomes with anti-HER2 therapy, primary and/or acquired resistance remain a major clinical challenge. Here, we sought to use a quantitative systems pharmacological (QSP) approach to evaluate the efficacy of lapa tinib (LAP), abemaciclib (ABE) and 5-fluorouracil (5-FU) mono- and combination therapies in JIMT-1 cells, a HER2+ BC cell line exhibiting intrinsic resistance to trastuzumab. Concentration–response relationships and temporal profiles of cellular viability were assessed upon exposure to single a gents and their combinations. To quantify the nature and intensity of drug-drug interactions, pharmacodynamic cellular response models were generated, to characterize single agent and combination time course data. Temporal changes in cell-cycle phase distributions, intracellular protein signaling, and JIMT-1 cellular viability were quantified, and a systems-based protein signaling network model was developed, integrating  protein dynamics to drive the observed changes in cell viability. Global sensitivity analyses for each treatment arm were performed, to identify the most influential parame ters governing cellular responses. Our QSP model was able to adequately characterize protein dynamic and cellular viability trends following single and combination drug exposure. Moreover, the model and subsequent sensit...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research