Abstract 5607: TLE4 is a key modulator of resistance to mTOR pathway specific inhibition in glioblastoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Rapamycin, a selective inhibitor of TOR (target of rapamycin), has been used in clinical trials for the treatment of glioma (Cloughesy et al., 2008). However, even though some patients respond temporarily to rapamycin treatment, virtually all recur. The mechanisms underlying this resistance to therapy are unknown. Here, we utilized patient-derived glioblastoma (GBM) neurosphere cultures to examine these mechanisms. GBM cell cultures exposed to chronic rapamycin yield a population of rapamycin resistant cells with an increased malignant phenotype upon removal from treatment, enhanced sphere formation in vitro and enhanced tumorigenesis. We used an unbiased, proteomics-based approach to discover phosphopeptides that were upregulated during rapamycin treatment in vitro. Amongst the peptides that we uncovered was Tle4/Groucho, a global co-repressor and known modulator of several key signaling pathways, including the Wnt and Notch pathways. In an expression microarray, Tle4 was found to be significantly upregulated within chronic rapa treated GBM cells. We show that TLE4 is a key modulator of resistance to mammalian target of rapamycin (mTOR) pathway specific inhibition. While TLE4 knockdown has no clear effect on naive cells, this knockdown promotes sensitivity under chronic rapamycin treatment as evidenced by reduced neurosphere formation. TLE4 mediate rapamycin resistance through activation of the quiescent population. Our results indicate that chronic mTOR specific inhibition imparts TLE4 mediated resistance through both ERK activation and inhibition of mTOR. The identification of this role for TLE4 in rapamycin resistance provides a novel target for mTOR pathway-associated chemotherapeutic agents. References: Cloughesy, T.F., Yoshimoto, K., Nghiemphu, P., Brown, K., Dang, J., Zhu, S., Hsueh, T., Chen, Y., Wang, W., Youngkin, D., et al. (2008). Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5, e8. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5607. doi:1538-7445.AM2012-5607