Abstract B158: Targeting cell survival pathways in glioblastoma.

Abstract

Abstract Summary: Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumour in adults. Patients diagnosed with GBM have a mean time of survival of 1 year after diagnosis and treatment, with a 5 year overall survival rate being just <5%. A classical hallmark of any cancer is deregulated cell survival and GBM has been known to associate with mutations in a number of growth factor and cytokine receptors, including the Fibroblast Growth Factor (FGF) receptor (FGFR), which leads to deregulated survival. We have previously identified a phospho-tyrosine-independent mechanism by which FGFR1 and FGFR2 promote cell survival whereby Ser779 phosphorylation within the cytoplasmic tail of the receptor is essential for initiating signals that promote phosphatidyl inositol 3-OH kinase (PI3K) and Ras-Mitogen activated protein kinase (MAPK) activation. We now show that this novel Ser779-mediated cell survival pathway is deregulated in glioblastoma cell lines. Specifically, Ser779 is constitutively phosphorylated in U118 and U251 glioblastoma cell lines. Consistent with this constitutive Ser779 phosphorylation, we found deregulation of down-stream signalling targets of Ser779 including Akt phosphorylation and GSK3 phosphorylation. Importantly, while pharmacological blockade of FGFR signalling using the FGFR tyrosine kinase inhibitor was able to block FGF-mediated cell proliferation in glioblastoma cell lines, it did not significantly affect autonomous cell survival. Thus while FGFR-mediated phospho-tyrosine signalling is clearly involved in cell proliferation, our results would suggest that the Ser779 signalling is important for regulating cell survival. We therefore sought to block signalling targets downstream of Ser779 in glioblastoma cell lines. To further dissect the contribution of FGFR2-Ser779 phosphorylation and downstream PI3K signalling to the survival of glioblastoma, we treated these cells with a panel of inhibitors of various signalling pathways. The two key signalling pathways that we targeted were the PI3K and MAPK pathways, along with using pan Ser-Thr and pan-Tyr inhibitors. We used inhibitors of GSK3, Akt and mTor, as well as PI3K p110 isoform-selective inhibitors for the PI3K pathway. For the MAPK pathways we used inhibitors of MEK, p38 and JNK. Importantly, we have shown that targeting the PI3K p110 (but not β, δ or γ), results in inhibition of Akt phosphorylation. In particular, we have found that one PI3K p110α-selective inhibitor is able to induce potent apoptosis of gliomas, which cannot be rescued by growth factor treatment. Our results show that the FGF receptor Ser779-PI3K p110 pathway is deregulated in glioblastoma and that selective targeting of this pathway may provide therapeutic benefit by inducing apoptosis in malignant cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B158.