Simplifying the complexity of resistance heterogeneity in metastasis

• Drug resistance can be modeled as either a discrete or continuous phenomenon.
• The integration of heterogeneity, cellular rates, and density impacts upon cancer growth.
• Density-dependence versus exponential growth results in different degrees of heterogeneity.

The main goal of treatment regimens for metastasis is to control growth rates, not eradicate all cancer cells. Mathematical models offer methodologies that incorporate high-throughput data with dynamic effects on net growth. The ideal approach would simplify, but not over-simplify, a complex problem into meaningful and manageable estimators that predict the response of a patient to specific treatments. We explore here three fundamental approaches with different assumptions concerning resistance mechanisms in which the cells are categorized into either discrete compartments or described by a continuous range of resistance levels. We argue in favor of modeling resistance as a continuum, and demonstrate how integrating cellular growth rates, density-dependent versus exponential growth, and intratumoral heterogeneity improves predictions concerning the resistance heterogeneity of metastases.