A novel complex comprising BRaf, PKCϵ and S6K2 mediates the pro-survival effects of FGF-2 in small cell lung cancer cells

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 2522 Patients with small cell lung cancer (SCLC) die because of chemoresistance. We have previously shown that fibroblast growth factor-2 (FGF-2) increases the translation and thereby the expression of antiapoptotic proteins, XIAP and Bcl-XL and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multi-protein complex comprising B-Raf, PKCϵ and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCϵ or S6K2 abolishes FGF-2-mediated survival. In contrast, over-expression of PKCϵ increases XIAP and Bcl-XL levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-XL and pro-survival effects. However, increased S6K1 kinase activity has no such effect. The prosurvival effects of this complex were also seen in HEK293 cells. Moreover, RNAi mediated knockdown of B-Raf, PKCϵ and S6K2 but not S6K1 impaired clonogenic growth of breast and non-small cell lung cancer cells. Thus, S6K2 but not S6K1 mediates pro-survival/chemoresistance signalling. Intriguingly, the immunohistochemical expression levels of S6K2 in lung cancer biopsy specimens appeared to correlate with subsequent resistance to therapy. In conclusion, this FGF-2-mediated pathway may predict chemoresistance and provide new targets for novel therapeutics.