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The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells
| Content Provider | SAGE Publishing |
|---|---|
| Author | Mumenthaler, Shannon M. Foo, Jasmine Choi, Nathan C. Heise, Nicholas Leder, Kevin Agus, David B. Pao, William Michor, Franziska Mallick, Parag |
| Copyright Year | 2015 |
| Abstract | Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times, demonstrating that these endpoints are strongly dependent on the microenvironment. Our interdisciplinary approach provides a model system to quantitatively investigate the impact of microenvironmental effects on the evolutionary dynamics of tumor cells. |
| Related Links | https://journals.sagepub.com/doi/pdf/10.4137/CIN.S19338?download=true |
| ISSN | 11769351 |
| Volume Number | 14s4 |
| Journal | Cancer Informatics (CIX) |
| e-ISSN | 11769351 |
| DOI | 10.4137/CIN.S19338 |
| Language | English |
| Publisher | Sage Publications UK |
| Publisher Date | 2015-07-15 |
| Publisher Place | London |
| Access Restriction | Open |
| Rights Holder | © 2015 SAGE Publications. |
| Subject Keyword | cancer microenvironment evolutionary modeling drug resistance |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology |
