Abstract 4578: Identification of a gene expression signature that is associated with dependency on FGFR3 rather than EGFR in bladder cancer cells
Authors: Cheng Tiewei , Roth Beat , McConkey David J. 
Published: August 2012

Activating mutations in the type-3 receptor of fibroblast growth factors (FGFR3) are present in a large subset of human bladder cancers. In addition, the epidermal growth factor receptor (EGFR) is overexpressed as a function of progression in bladder cancer, and EGFR inhibitors are being evaluated in Phase II clinical trials. However, in previous studies we found that human bladder cancer cells display marked heterogeneity in their sensitivities to EGFR inhibitors and demonstrated that epithelial-to-mesenchymal transition (EMT) is involved in resistance. Nonetheless, many “epithelial” bladder cancer cells are resistant to EGFR inhibitors, suggesting that proliferation in these cells may be driven by another growth factor receptor. To more precisely define this biological heterogeneity, we screened a panel of human urothelial cancer cells using small molecule EGFR or FGFR inhibitors and correlated responses to baseline whole genome mRNA expression profiles. A panel of 25 human urothelial cancer cells was tested for the anti-proliferative effects of AZD4547 by MTT. We identified 5 cell lines(RT4, RT112, UM-UC1, UM-UC14, SW780) strongly inhibited by ≤ 1 μM of the drug. Similarly, we identified 4 cell lines (UM-UC4, UM-UC5, UM-UC9, and UM-UC16) were sensitive to ≤ 1 μM gefitinib. Strikingly, cells displayed mutually exclusive sensitivities to AZD4547 or gefitinib, and combinations of the drugs didn't further increase growth arrest. Furthermore, AZD4547 sensitivity was not closely linked to FGFR3 mutational status: 4/5 of the sensitive cell lines expressed wild-type FGFR3, and gefitinib-sensitive UM-UC16 cells expressed an activating (S249C) mutation. All cells sensitive to either AZD4547 or gefitinib were confined to the “epithelial” subgroup which was characterized by high expression of E-cadherin and low expression of Zeb-1. Using Illumina whole genome arrays to comparing gene expression profile between FGFR sensitive and EGFR sensitive cells, we found that active PPAR signaling, particularly high baseline expression of the PPAR target gene FABP4, characterized the FGFR3-dependent cells. We further investigated whether PPAR could regulate FABP4 expression in FGFR dependent cells through knocking down specific genes of interests by siRNA. We found that among three isoforms of PPARs, PPARδ has more effect than PPARδ, ≤ to down-regulate FABP4 in UM-UC14 and RT4. In summary, sensitivity to the anti-proliferative effects of EGFR and FGFR inhibitors is confined to the “epithelial” subset of human bladder cancer cells. Within the epithelial subset, sensitivity to EGFR or FGFR inhibitors is mutually exclusive. Mutational activation of FGFR3 doesn't correlate well with sensitivity to FGFR inhibition. Rather, FGFR-dependent cells express high levels of FABP4 and other genes associated with PPAR signaling.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4578. doi:1538-7445.AM2012-4578