Combining Multiscale Experimental and Computational Systems Pharmacological Approaches to Overcome Resistance to HER2-targeted Therapy in Breast Cancer.

Emergence of HER2 therapy resistance in HER2-positive breast cancer (BC) poses a major clinical challenge. The primary mechanisms of resistance include aberrant activation of the HER2 and PI3K/Akt/mTOR pathways. The existence of feedback loops in this pathway may engender resistance to targeted therapies such as everolimus, an mTOR inhibitor, resulting in a more aggressive form of refractory HER2+BC. Here, we hypothesize that a triple and sequential combination therapy of paclitaxel, a potent cytotoxic agent, prior to concomitant administration of dasatinib, a Src family kinase inhibitor, with everolimus, restores sensitivity to treatment in refractory HER2+BC. This was assessed by a combination of experimental and computational approaches. Quantitative systems pharmacological (QSP), pharmacokinetics (PK), and pharmacodynamics (PD) studies were conducted in static and three-dimensional and dynamic (3DD) cell culture systems using a HER2-positive cell line resistant to HER2 therapy, JIMT-1. Dynamic responses in cellular viability and key signaling proteins in the HER2 and PI3K/Akt/mTOR pathways were measured upon treatments with single drugs, combinations, and appropriate controls. A QSP-PK/PD model was developed and used to optimize the sequence and inter-dose interval of the three agents in the combination. The proposed sequential combination therapy demonstrated strong cytotoxic effects in JIMT-1 cells, and our models predicted the usefulness of this combination over prolonged durations in the 3DD setting. Our combined experimental and QSP-PK/PD modeling approach may serve as a useful screening tool in predicting clinical efficacy of combination therapies in oncology. Nonetheless, further in vivo human xenograft tumor studies are warranted.