Abstract 1463: Pharmacological impact of epithelial-mesenchymal plasticity in the H358 lung tumor model

Abstract

Abstract The phenotypic changes associated with epithelial to mesenchymal transition (EMT) give tumor cells at least two attributes that increase metastatic efficiency. First, mesenchymal cells have lost cell-cell contacts and are more invasive and can therefore escape the primary tumor, whereas epithelial cells remain anchored by cell-cell contacts in the primary tumor. Second, mesenchymal cells in vitro are less sensitive than epithelial cells to agents that inhibit the EGFR pathway. This appears to translate into the clinic, since patients with tumors that express mesenchymal markers do not respond to EGFR targeting therapeutics as well as patients with more epithelial tumors. To determine whether we can control sensitivity to EGFR inhibitors by manipulating a cell's epithelial/mesenchymal status, we examined the role of EMT and its reversibility in tumor cell sensitivity to the EGFR inhibitor erlotinib. We studied in vitro models of EMT driven by Transforming Growth Factor β (TGFβ), Hepatocyte Growth Factor + Oncostatin M (HGF+OSM), Snail or Zeb1 in the H358 non-small cell lung carcinoma model. EMT driven by TGFβ or HGF+OSM caused a significant decrease in sensitivity to erlotinib, while EMT driven by induced expression of Snail or Zeb1 was much less effective, suggesting a change in drug sensitivity requires more input than these canonical EMT transcription factors. Once mesenchymal tumor cells have localized to a metastatic site, it is thought the tumor cells must undergo a mesenchymal to epithelial transition (MET) in order to form a cohesive tumor. We examined the reversibility of EMT in our models and the corresponding erlotinib sensitivity, both by withdrawal of ligand and by pharmacological inhibition of the signaling pathways downstream of the drivers. Using these approaches, we found EMT driven by HGF+OSM was reversible as evidenced by morphology and marker changes, and this reversion correlated with an increase in erlotinib sensitivity, comparable to the parental H358 cells. EMT driven by TGFβ was partially reversed by both ligand withdrawal and pharmacological inhibition of the receptor, and the extent of reversion in erlotinib sensitivity correlated with the extent of marker reversion. These results demonstrate that the extent of reversibility of EMT is dependent on the driver. Furthermore, it may be possible to drive some erlotinib-insensitive tumors back to a more erlotinib-sensitive state with pharmacological agents, thus improving patient response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1463.