Understanding and Targeting the FGF-2/S6K2 Signal Pathway in Small Cell Lung Cancer Towards the Development of Novel Anti-Cancer Treatments.

Small Cell Lung Cancer (SCLC) cells activate a signal pathway in response to chemotherapy, as a result the cancer rapidly develops chemoresistance. Since the late 1980’s SCLC has a poor prognosis with a 5 year survival rate of only 5%, highlighting the need for novel therapeutic intervention. This pathway is initiated by Fibroblast Growth Factor 2 (FGF-2) binding its cognate receptor, Fibroblast Growth Factor Receptor 1 (FGFR-1). Downstream of receptor activation a signal complex forms consisting of three kinases – B-Raf, Protein Kinase C epsilon (PKCε) and Ribosomal S6 Kinase Beta II (S6K2) – resulting in the activation of the latter. S6K2 then phosphorylates the nucleic acid binding protein Heterogeneous Nuclear Ribonucleoprotein A1 (hnRNP A1) at serines 4 and 6. The phosphorylated hnRNP A1 then binds two anti-apoptotic mRNAs, XIAP and Bcl-X L , believably at Internal Ribosome Entry Sites (IRES) in the mRNAs 5‘ Untranslated Regions (UTR). The hnRNP A1-bound mRNAs are then shuttled to the cytoplasm where they are translated in a 5‘ cap-independent manner following ribosomal recruitment by the IRES structures. Insight into how these proteins interact and function at the atomic level is crucial to the understanding of the FGF2/S6K2 pathway. It should follow that this would ultimately provide the foundations for the development of novel therapeutics, which would ideally work to surpass or complement existing treatments, or at the very least, alleviate symptoms. Consequently, the aim of this PhD was to use structural and biophysical techniques to gain a better understanding of the mechanisms of cell survival signalling, identify candidate hnRNP A1 binding sites on the XIAP mRNA, and perform novel drug fragment screening with hnRNP A1.