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

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

Molecular cancer research : MCR (2014-05-03)
Jaime Acquaviva, Suqin He, Chaohua Zhang, John-Paul Jimenez, Masazumi Nagai, Jim Sang, Manuel Sequeira, Donald L Smith, Luisa Shin Ogawa, Takayo Inoue, Noriaki Tatsuta, Margaret A Knowles, Richard C Bates, David A Proia
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 glucuronidation-dependent metabolism and subsequent efflux of ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DL-Glyceraldehyde 3-phosphate solution, 45-55 mg/mL in H2O
Sigma-Aldrich
17-(Allylamino)-17-demethoxygeldanamycin, ≥98% (HPLC), solid
Propofol, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
2,6-Diisopropylphenol, 97%
Propofol for peak identification, European Pharmacopoeia (EP) Reference Standard