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


CONCLUSIONS
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.
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Jaime
J
Acquaviva
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Suqin
S
He
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Chaohua
C
Zhang
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
John-Paul
JP
Jimenez
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Masazumi
M
Nagai
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Jim
J
Sang
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Manuel
M
Sequeira
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Donald L
DL
Smith
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Luisa Shin
LS
Ogawa
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Takayo
T
Inoue
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Noriaki
N
Tatsuta
Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, United Kingdom.
Margaret A
MA
Knowles
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
Richard C
RC
Bates
Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and dproia@syntapharma.com.
David A
DA
Proia
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011897:Random Allocation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3