Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Authors

Jinyan Shen, University of Rhode Island
Li Li, University of Rhode Island
Tao Yang, University of Rhode Island
Paul S. Cohen, University of Rhode IslandFollow
Gongqin Sun, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2-13-2020

Department

Cell & Molecular Biology

Abstract

Quantifying the response of cancer cells to a drug, and understanding the mechanistic basis of the response, are the cornerstones for anti-cancer drug discovery. Classical single target-based IC₅₀ measurements are inadequate at describing cancer cell responses to targeted drugs. In this study, based on an analysis of targeted inhibition of colorectal cancer cell lines, we develop a new biphasic mathematical model that accurately describes the cell–drug response. The model describes the drug response using three kinetic parameters: ratio of target-specific inhibition, F₁, potency of target-specific inhibition, K_d1, and potency of off-target toxicity, K_d2. Determination of these kinetic parameters also provides a mechanistic basis for predicting effective combination targeted therapy for multi-driver cancer cells. The experiments confirmed that a combination of inhibitors, each blocking a driver pathway and having a distinct target-specific effect, resulted in a potent and synergistic blockade of cell viability, improving potency over mono-agent treatment by one to two orders of magnitude. We further demonstrate that mono-driver cancer cells represent a special scenario in which F₁ becomes nearly 100%, and the drug response becomes monophasic. Application of this model to the responses of >400 cell lines to kinase inhibitor dasatinib revealed that the ratio of biphasic versus monophasic responses is about 4:1. This study develops a new mathematical model of quantifying cancer cell response to targeted therapy, and suggests a new framework for developing rational combination targeted therapy for colorectal and other multi-driver cancers.

Citation/Publisher Attribution

Shen, J.; Li, L.; Yang, T.; Cohen, P.S.; Sun, G. Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells.Cancers 2020, 12, 436. https://doi.org/10.3390/cancers12020436

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.