Cancer-Associated Fibroblast Driven Drug Resistance In Colorectal Cancer

Drug resistance remains a major problem in the treatment of most cancers. For example, KRAS wild-type colorectal cancers (CRCs) are typically treated with the anti-epidermal growth factor receptor (EGFR) therapy cetuximab in combination with standard chemotherapy; however, of the 40% of patients that do respond, virtually all relapse within 3-12 months. Additionally, around 25% of nonresponders have no identifiable resistance mechanisms. This suggests that it is not just cell-intrinsic mechanisms that result in resistance, but that extrinsic factors play a role. The purpose of this study was to investigate how the dynamics of the tumor microenvironment, specifically cancer-associated fibroblasts (CAFs) and hypoxia, modify the response of CRC cells to cetuximab. We used a novel high-content imaging platform to generate quantitative phenotypic data (i.e. morphology, birth/death rates) of cellular co-cultures perturbed by multiple, co-occurring microenvironmental conditions. Preliminary data demonstrated reduced sensitivity of tumor cells to cetuximab in the presence of CAFs, which was dependent on patient specifics and time scale of co-culture. Additionally, we found that low oxygen conditions altered the effect of CAFs on tumor cell phenotypes, which highlights the importance of studying co-occurring microenvironmental factors. This work underlies the importance of considering not just the genetic makeup of patient tumors, but also the heterogeneity of the surrounding microenvironment when designing personalized treatment strategies. Citation Format: Colleen M. Garvey, Oscar Chen, Shannon M. Mumenthaler. Cancer-associated fibroblast driven drug resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5908. doi:10.1158/1538-7445.AM2017-5908