Abstract 1845: Sensitivity of PC9 cells to erlotinib is affected by extracellular matrix

Abstract

Abstract Tyrosine kinase inhibitors of epidermal growth factor receptor, such as erlotinib and gefinitib, have been effective in the initial treatment of non-small cell lung cancer. With time, however, initially responsive tumors almost invariably rebound and proliferate under therapy. Of general interest is the impact of tumor cell heterogeneity on rebound time. Previously, we isolated 89 single-cell derived discrete sublines (DS) from the commonly studied PC9 cell line by monitoring the distribution of cell fates (division, quiescence, and cell death) and the drug-induced proliferation (DIP) rate under erlotinib treatment. In this work we examine the role of the extracellular matrix (ECM) in determining proliferation behavior and the distribution of cell fates. Cells suspended in 3D matrices show increased sensitivity to erlotinb with the rate of cell death depending on the ECM composition. DS sublines that were highly resilient in 2D culture (i.e., positive DIP rate and <10% cell death under treatment) asymptote to about 40% cell death in Matrigel after ten days in 1 µM erlotinb. Both the rate of cell death and the total percentage of the cell population that dies increased in collagen I and in collagen I coated hydrogel. At asymptotic levels, the cell population contained both dividing and quiescent cells. In contrast, DS sublines with negative DIP rates in 2D culture reached 90-99% cell death in each ECM considered. We conclude that the pathways conferring resilience in these cells are sensitive to ECM conditions. Intriguingly, we find that resilient DS sublines tend to have diversity in cluster morphologies in the matrices, suggesting a possible correlation between ECM engagement and/or adhesion and resilience. Molecular studies should clarify mechanistic relationships between ECM and sensitivity to targeted therapy, and whether such relationship may extend to clinical tumors. Citation Format: Halina M. Onishko, Jie Zhao, Katherine L. Jameson, Peter L. Frick, Darren R. Tyson, Vito Quaranta, Thomas E. Yankeelov, Erin C. Rericha. Sensitivity of PC9 cells to erlotinib is affected by extracellular matrix. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1845. doi:10.1158/1538-7445.AM2014-1845