Abstract 602: BEZ235 efficacy in 3D-cancer cell line screening

Abstract In vitro efficacy assessment of drugs in panels of tumor-derived cell lines has proven to be a powerful tool for predictive biomarker discovery. However, in the last few years it has become evident that particularly for tumor cell lines derived from solid tumors, the results do not always correlate with what is seen in xenografts as well as clinically. One of the reason is that traditionally these type of studies are done in monolayers (2D), which lack the complexity normally seen in vivo. 3D cultures offer the ability to carry out the same type of studies with the added benefit of incorporating 3-dimensional cellular interactions and physiological gradients, normally seen in a tumor microenvironment. In this study, we evaluated the efficacy of BEZ235, an imidazoquinoline, targeting the phosphatidylinositol 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR). BEZ235 was evaluated in a panel of 60 cell lines grown as spheroids, and this information was used to investigate genes associated with sensitivity. Cell lines grown as spheroids proved to be highly sensitive to the drug, where 45 of 60 cell lines showed an IC50 lower than 1 μM. Biomarker association analysis identified two mutated genes associated to BEZ235 sensitivity. The first biomarker was the phosphatase and tensin homolog (PTEN) a tumor suppressor gene, that when deregulated plays an important role in the development of several cancers. The second biomarker was AXIN1, a negative regulator of the WNT signaling pathway, and its deregulation has been associated with hepatocellular carcinoma. Since both PTEN and AXIN1 are thought to play a role in tissue invasion and metastasis, we studied the ability of BEZ235 to inhibit cellular invasion, and the results are discussed. Citation Format: Macarena Irigoyen, Gonzalo Castillo. BEZ235 efficacy in 3D-cancer cell line screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 602.