FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism.

Autor:	Acquaviva J; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., He S; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Zhang C; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Jimenez JP; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Nagai M; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Sang J; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Sequeira M; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Smith DL; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Ogawa LS; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Inoue T; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Tatsuta N; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Knowles MA; Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, United Kingdom., Bates RC; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and., Proia DA; Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and dproia@syntapharma.com.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2014 Jul; Vol. 12 (7), pp. 1042-54. Date of Electronic Publication: 2014 Apr 30.
DOI:	10.1158/1541-7786.MCR-14-0004
Abstrakt:	Unlabelled: 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 glucuronidation-dependent metabolism and subsequent efflux of ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity. Implications: Pharmacologic blockade of the molecular chaperone HSP90 represents a promising approach for treating bladder tumors driven by oncogenic gene rearrangements of FGFR3. Furthermore, UDP-glucuronosyltransferase enzyme expression may serve as a predictive factor for clinical response to resorcinol-based HSP90 inhibitors. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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