Abstract PR16: Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance

Abstract

Abstract Tumor growth is a complex evolutionary process driven by dynamic feedback between a heterogeneous cell population and selection pressures from the tumor microenvironment. Spatio-temporal heterogeneity in the microenvironment can create physical niches that facilitate cellular adaptation as seen in regions of hypoxia and acidosis where cells may up-regulate glycolysis and become resistant to acid-meditated toxicity in order to survive. In recent studies, using clinically prevalent subtypes of EGFR-related non-small cell lung cancer (NSCLC), we observe that nutrient and drug gradients resulting from a cells' proximity to vasculature, can produce selective pressures driving tumor evolution. We provide a detailed examination of the microenvironmental impact (i.e. oxygen, glucose, and drug) on growth rates of NSCLC cell lines that are either sensitive or resistant to the EGFR TKI, erlotinib. Often we consider drug resistance to be associated with a fitness cost to the cell in the absence of drug. However, here we demonstrate that the situation is more complex, with the local tumor microenvironment influencing the magnitude and the directionality of the selective effect. In fact, the resistant cells actually gain a selective advantage in nutrient-stressed environments compared to the sensitive cells. The resulting growth dynamics were used to inform a stochastic compartment-based tumor model of pre-existing drug resistance where each compartment represents a specific tumor environmental niche. This integrative modeling framework was then used to predict rebound growth kinetics and tumor composition (i.e. % resistance) and in particular, provide insight into the magnitude by which the microenvironment influences these results. These investigations strongly suggest that ignoring the microenvironment or using laboratory environmental conditions to inform tumor dynamics can lead to inaccurate conclusions. Therefore, knowledge of the selective advantage/disadvantage of different cell populations within different regions of the tumor will better guide model predictions, influence overall tumor dynamics, and impact treatment strategies. This abstract is also presented as Poster A80. Citation Format: Shannon Mumenthaler, Jasmine Foo, Nathan Choi, William Pao, David Agus, Franziska Michor, Parag Mallick. Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR16. doi:10.1158/1538-7445.CHTME14-PR16