Abstract 1134: RNAi screening of human kinome identified fibroblast growth factor receptor 4 (FGFR4) as potential molecular target in basal-like breast cancers (BLBC).

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Global gene expression profiling has uncovered previously unrecognized subsets of human breast cancer, including the so-called triple-negative or tumours (BLBC) characterized by estrogen/progesterone receptor negativity, lack of Her-2/Neu amplification and high frequency of p53 mutation. These refractory tumours therefore are insensitive to hormonal therapy or trastuzumab-based therapy, and thus confer a markedly poor prognosis relative to other subtypes. To date, little progress has been made to identify specific molecular pathways associated with these refractory cancers that may be effectively targeted for therapeutic purposes. Using a human kinome RNAi library screen, we show that knock-down of endogenous human FGFR4 (but not FGFR1-3) induces significant tumor-specific cell death in basal-like breast cancer cells. Further analysis reveals that FGFR4 mediates the BLBC cells survival through activation of AKT as knock-down of endogenous FGFR4 in MDA-MB-468 and HCC1937 cells significantly reduced AKT phosphorylation. Consistently, ectopic expression of a constitutively active myristoylated AKT completely abrogates the apoptosis induced by FGFR4 knock-down. Interestingly, both MDA-MB-468 and HCC1937 also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. RNAi-mediated silencing of FGF19 evidently suppresses the growth of these BLBC cells via AKT signalling as marked by diminished AKT phosphorylation following depletion of FGF19. Knockdown of FGF19 in addition triggers ERK1/2 activation to compensate for AKT signalling down-regulation in MDA-MB-468. Together, our results demonstrated the existence of a FGFR4-FGF19 autocrine loop which could potentially be developed as therapeutic target for future treatment of BLBC. Citation Format: Kai Hung Tiong, Boon Shing Tan, Heng Lungh Choo, Ammu Kutty Radhakrishnan, Rozita Rosli, Soon-Keng Cheong, Chee-Onn Leong. RNAi screening of human kinome identified fibroblast growth factor receptor 4 (FGFR4) as potential molecular target in basal-like breast cancers (BLBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2013-1134