Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment

Author:

Greene James M.1,Gevertz Jana L.2,Sontag Eduardo D.34

Affiliation:

1. Rutgers University, New Brunswick, NJ

2. The College of New Jersey, Ewing Township, NJ

3. Northeastern University, Boston, MA

4. Harvard Medical School, Cambridge, MA

Abstract

Purpose Drug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise from random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself via either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols. Materials and Methods To better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance. Results Our model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable and propose an in vitro protocol that could be used to determine a treatment’s propensity to induce resistance.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

General Medicine

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