Drug profiling of cancer cell lines is a useful tool for predictive biomarker discovery, traditional done in two-dimensional cultures, a growing body of evidence suggests that results cannot always be translated into xenografts or in the clinic due to the lack of complexity of the culture conditions. 3D cultures offer the ability to carry out the same type of studies with the added benefit of incorporating the 3-dimentional cellular interactions and physiological gradients normally seen in a tumor microenvironment. In this study we used Numira's 3D cell line screening platform on Gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR). We determined IC50 of Gefitinib in a panel of 60 cell lines grown as spheroids and used this information to investigate genes associated with sensitivity. Two mutated genes were associated with sensitivity to Gefitinb, as expected, the epidermal growth factor receptor (EGFR) was one of them, since mutations on EGFR are required for clinical efficacy. The second gene was smoothened (SMO), a G protein-coupled receptor of the hedgehog signaling pathway. It has been suggested that blockade of the hedgehog signaling pathway enhances anti-proliferative effects of EGFR inhibitors, we explored this potential synergy in a combination studies of Gefitinib and SMO inhibitors, Cyclopamine and GDC0449, the results are discussed.
Citation Format: Gonzalo Castillo, Xiuyun Jiang. Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening. [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 5447. doi:10.1158/1538-7445.AM2015-5447