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FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism
Jaime Acquaviva1, Suqin He1, Chaohua Zhang1
1Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington, Massachusetts; and.
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.
Insights
Heat shock protein 90 (HSP90) inhibition shows promise for treating bladder cancers with FGFR3 gene rearrangements. UDP-glucuronosyltransferase enzyme levels may predict patient response to HSP90 inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Activating mutations and/or overexpression of FGFR3 are common in bladder cancer.
- FGFR3 gene rearrangements define a unique subset of bladder tumors, making FGFR3 a therapeutic target.
- Heat shock protein 90 (HSP90) is a molecular chaperone involved in stabilizing oncogenic proteins.
Purpose of the Study:
- To investigate the efficacy of the selective HSP90 inhibitor ganetespib in bladder cancer models with FGFR3 alterations.
- To compare ganetespib's effects with a pan-FGFR tyrosine kinase inhibitor (BGJ398).
- To explore mechanisms of resistance and potential predictive biomarkers for HSP90 inhibitor response.
Main Methods:
- Treatment of bladder cancer cell lines (RT112, 97-7, MHG-U3, RT4, SW480) with ganetespib, BGJ398, 17-AAG, 17-DMAG, and AUY922.
- Assessment of FGFR3-TACC3 fusion protein expression and oncogenic signaling protein depletion.
- Evaluation of cytotoxicity and in vitro/in vivo combinatorial effects.
- Analysis of UDP-glucuronosyltransferase (UGT1A) enzyme expression and ganetespib metabolism.
Main Results:
- Ganetespib induced loss of FGFR3-TACC3 fusion protein and depleted oncogenic signaling proteins in RT112 cells, causing potent cytotoxicity.
- Ganetespib demonstrated broader effects on mitogenic and survival pathways and overcame resistance to FGFR inhibitors in mutant cells.
- Combinatorial treatment with ganetespib and BGJ398 showed synergistic benefits in vitro and in vivo.
- FGFR3 fusion-positive lines RT4 and SW480 showed resistance to ganetespib/AUY922 but sensitivity to other HSP90 inhibitors, linked to high UGT1A expression and rapid ganetespib metabolism.
Conclusions:
- Pharmacologic blockade of HSP90 is a promising strategy for bladder tumors driven by FGFR3 oncogenic gene rearrangements.
- High UDP-glucuronosyltransferase enzyme expression may predict clinical response to resorcinol-based HSP90 inhibitors, serving as a potential biomarker.
