Background: Lung cancer is the leading cause of cancer death in the world, mainly due to complex genetic events that characterize lung cancer, tumor heterogeneity and resistance to traditional and targeted treatments. Resistance may be explained by passive clonal selectivity, however, the propensity and variability of resistance suggests an active process of tumor plasticity. We hypothesize that tumor cells undergo an epithelial to mesenchymal transition as a mechanism of resistance to chemotherapy.

Results: The lung adenocarcinoma cell lines NCI-H1299, NCI-H358, and NCI-H441 were exposed to gradually increasing doses of docetaxel over 12-16 weeks. Chemoresistance emerged with a 10-15X increase in IC50 as compared to parental cells. With each treatment dose increase more than 50% of cells remained alive, suggesting bulk cell transformation. This resistance has been maintained for more than 20 generations after withdrawal of docetaxel. Morphologically, NCI-H358 and NCI-H441 chemoresistant cell lines lost their cobblestone architecture becoming more spindle-shaped. Using RT-PCR assays, there was increased expression of mesenchymal-related genes, vimentin (2.5-3.5X), twist (2-4X) and decreased expression of epithelial-related genes such as E-CAD (2-5X). Our previous data suggested that Notch activity plays a significant role in the EMT process, thus we evaluated Notch downstream genes expression by RT-PCR. We detected increase expression of Hey2 (2.5-3.5X), in NCI-H358 and NCI-H441 resistant cell lines as compared to parental cells. When chemoresistant cell lines were exposed to gamma secretase inhibitor, a Notch inhibitor, they became less invasive, epithelial-like and sensitive to docetaxel.

Conclusion: These data suggest that tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemotherapy resistance that is controlled through the Notch pathway. Inhibiting Notch activity induces mesenchymal to epithelial transition and re-sensitizes cells to chemotherapy. Notch inhibition in combination with standard chemotherapy represents a potential approach to achieve better disease control.

Citation Format: Khaled A. Hassan. Tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemoresistance that is reversed by Notch pathway inhibition in lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 739. doi:10.1158/1538-7445.AM2015-739

©2015 American Association for Cancer Research.
2015