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Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Combining Multiscale Experimental and Computational Systems Pharmacological Approaches to Overcome Resistance to
Tanaya R Vaidya1, Anusha Ande1, Sihem Ait-Oudhia2
1Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida.
Abstract:
The emergence of human epidermal growth factor receptor type-2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. The primary mechanisms of resistance include aberrant activation of the HER2 and phosphatidylinositol 3-kinase/mammalian target of rapamycin/AKT8 virus oncogene cellular homolog (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, before concomitant administration of dasatinib, a SRC proto-oncogene nonreceptor tyrosine kinase (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+ cell line resistant to HER2 therapy, JIMT-1. The 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 interdose 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.
Insights
A novel sequential combination therapy involving paclitaxel, dasatinib, and everolimus shows promise in overcoming resistance in HER2-positive breast cancer. This approach targets key signaling pathways to restore treatment sensitivity in refractory cases.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- HER2-positive breast cancer (BC) frequently develops resistance to HER2-targeted therapies.
- Key resistance mechanisms involve aberrant activation of HER2 and PI3K/Akt/mTOR pathways, with feedback loops contributing to treatment failure.
- Refractory HER2+ BC presents a significant clinical challenge, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate a sequential combination therapy of paclitaxel, dasatinib, and everolimus for refractory HER2+ BC.
- To assess the efficacy of this triple therapy in restoring sensitivity to treatment in HER2-targeted therapy-resistant cells.
- To utilize quantitative systems pharmacology (QSP) and pharmacokinetic/pharmacodynamic (PK/PD) modeling to optimize treatment sequencing and predict clinical utility.
Main Methods:
- Experimental studies using the HER2-resistant JIMT-1 cell line in static and 3D dynamic (3DD) culture systems.
- Quantitative systems pharmacology (QSP) modeling integrated with pharmacokinetic (PK) and pharmacodynamic (PD) analyses.
- Measurement of cellular viability and key signaling proteins in response to single agents and combination therapies.
Main Results:
- The sequential combination therapy demonstrated significant cytotoxic effects against HER2-resistant JIMT-1 cells.
- QSP-PK/PD modeling successfully optimized the sequence and interdose intervals of the therapeutic agents.
- Models predicted the potential for sustained efficacy of the combination therapy in a 3DD culture environment.
Conclusions:
- A sequential triple combination therapy of paclitaxel, dasatinib, and everolimus can overcome HER2 therapy resistance in breast cancer.
- The integrated QSP-PK/PD modeling approach serves as a valuable tool for predicting the clinical efficacy of combination therapies.
- Further in vivo studies are warranted to validate these findings in preclinical models.
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