FGFR3 Translocations in Bladder Cancer: Differential Sensitivity to HSP90 Inhibition Based on Drug Metabolism

Abstract

Activating mutations and/or overexpression of FGFR3 are common in bladder cancer, making FGFR3 an attractive therapeutic target in this disease. In addition, FGFR3 gene rearrangements have recently been described that define a unique subset of bladder tumors. Here, a selective HSP90 inhibitor, ganetespib, induced loss of FGFR3-TACC3 fusion protein expression and depletion of multiple oncogenic signaling proteins in RT112 bladder cells, resulting in potent cytotoxicity comparable with the pan-FGFR tyrosine kinase inhibitor BGJ398. However, in contrast to BGJ398, ganetespib exerted pleiotropic effects on additional mitogenic and survival pathways and could overcome the FGFR inhibitor-resistant phenotype of FGFR3 mutant-expressing 97-7 and MHG-U3 cells. Combinatorial benefit was observed when ganetespib was used with BGJ398 both in vitro and in vivo. Interestingly, two additional FGFR3 fusion-positive lines (RT4 and SW480) retained sensitivity to HSP90 inhibitor treatment by the ansamycins 17-AAG and 17-DMAG yet displayed intrinsic resistance to ganetespib or AUY922, both second-generation resorcinol-based compounds. Both cell lines, compared with RT112, expressed considerably higher levels of endogenous UGT1A enzyme; this phenotype resulted in a rapid glucuronidationdependent metabolism and subsequent efflux of ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity.

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

“…The existence of FGFR3-TACC3 fusions in human cancers creates additional challenges and opportunities for identifying effective treatment strategies. For instance, a recent study showed that the HSP90 inhibitor ganetespib exerted pleiotropic effects on mitogenic and survival pathways in cells expressing oncogenic gene rearrangements of FGFR3, and provided an alternative therapeutic approach in addition to the pan-FGFR tyrosine kinase inhibitor BGJ398 (47). Further study of novel pathways activated by the FGFR3-TACC3 fusion protein, and a deeper understanding of the molecular details exploited by FGFR3-TACC3 to achieve its biologic potency, can be expected lead to novel therapeutic paradigms.…”

“…Received December 22, 2015; revised January 12, 2016; accepted February 3, 2016; published OnlineFirst February 11, 2016. …”

HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors

“…insensitive to resorcinol-based HSP90 inhibitors due to endogenous glucoronidation (27). STA-12-8666 treatment significantly suppressed SW780 tumor growth (Fig.…”

Phenotypic and Signaling Consequences of a Novel Aberrantly Spliced Transcript FGF Receptor-3 in Hepatocellular Carcinoma

“…Activation and dimerization of FGFR3 result in cell proliferation or differentiation via signal transduction pathways (10). Point mutations in transmembrane domain of FGFR3 have been identified as a causative factor for skeletal development disorders such as achondroplasia and hypochondroplasia (7,30).…”

“…Two membrane-proximal D2 and D3 domains, and interconnecting D2-D3 linker bear the determinants of ligand binding and specificity (10). The Ig-domain III is encoded by two separate exons, exon 8 and exon 9.…”