Abstract 4628: The RSK inhibitor SL0101 impairs the proliferation of glioblastoma cell lines

Abstract

Abstract Glioblastoma (GBM) is the most common and lethal type of brain tumor. The most frequently altered signaling pathway in this tumor is the RTKs-PI3K-Akt-mTORC1 (88% of cases). However, clinical trials for GBM using inhibitors of this pathway exhibited poor clinical responses. One of the main responsibles for this resistance is the compensatory activation of the Ras-ERK1/2 pathway. In fact, GBMs can also present alterations in the Ras-ERK1/2 pathway, such as mutation of NF1 in 18% of the cases. RSK is a direct target of ERK1/2 and has been shown to regulate important functions in different types of tumors, such as prostate and breast. RSK is a family of kinases comprised by four highly-homologous isoforms in humans (RSK1-4) and nothing is known about their functions in GBMs. Here we show that RSK1 levels are highly variable between cells, the levels of RSK2 are less variable, and RSK3 and RSK4 were not detected. To gain insight into the function of RSK, we studied the effects of the RSK inhibitor, SL0101, on the proliferation of four different GBM cell lines (LN18, LN229, U87MG and A172). A suboptimal concentration of SL0101 (50 μM) was able to inhibit basal and EGF-stimulated proliferation, and it was more potent than 100 nM rapamycin in some of the cells. In 3 of the cell lines, SL0101 inhibited serum-stimulated proliferation, and in 2 of them, it was more potent than rapamycin. We have previously shown that SL0101 can inhibit mTORC1 signaling in an ERK1/2-RSK independent manner. However, SL0101 showed a synergistic interaction with rapamycin in all of the cell lines, which suggests that other effects besides RSK-mTORC1 inhibition might be involved in the effect of SL0101. This was further suggested by the modest synergistic interaction between rapamycin and the RSK inhibitor, fmk. Altogether, these results indicate that SL0101 is a potent inhibitor of proliferation in a manner not related with the RSK1 status of GBM cells. Further studies to define the molecular mechanism of the effects of SL0101 are necessary to understand which pathways are indeed modulated. Citation Format: Martín Roffe, Fernanda C. Lupinacci, Luana C. Soares, Glaucia N. Hajj, Vilma R. Martins. The RSK inhibitor SL0101 impairs the proliferation of glioblastoma cell lines. [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 4628.