Abstract C130: The Hsp90 inhibitor ganetespib promotes the degradation of FGFR3 in bladder cancer models and induces regression in tumors harboring oncogenic FGFR3 fusions.

Background: Fibroblast growth factor receptor 3 (FGFR3) is activated by point mutation, chromosomal rearrangement, and/or receptor overexpression in a high percentage of bladder cancers, making FGFR3 an attractive therapeutic target for bladder cancer. Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability of FGFR3 and hundreds of other kinases and oncoproteins (termed “client proteins”), many of which are known to support tumorigenesis. Ganetespib is a selective inhibitor of Hsp90 currently being evaluated in several clinical trials, including a pivotal Phase 3 study. Here, we investigated the preclinical activity of ganetespib in bladder cancer models expressing FGFR3, as monotherapy or in combination with an FGFR inhibitor.

Results: Ganetespib displayed strong anticancer activity across a panel of 20 bladder cancer cell lines with diverse genetic backgrounds (mean EC50 = 38 nM), including those overexpressing wt FGFR3 or FGFR3 fusions. Notably, ganetespib was 10 times more potent than the selective FGFR3 inhibitor BGJ398 in bladder cancer cells with activating mutations in FGFR3. At the molecular level, ganetespib induced the rapid destabilization of full-length FGFR3 and the FGFR3-TACC3 fusion protein within 4 hours suggesting that FGFR3 is a highly sensitive Hsp90 client. Consequently, MAPK and AKT/mTOR signaling were suppressed, resulting in apoptosis evident by decreased levels of P-BAD and an increase in BIM, cleaved Caspase-3, and PARP expression. In vivo, ganetespib treatment led to tumor regression in RT112 xenografts coordinate with the deactivation of FGFR3-TACC3, as well as numerous other client proteins and their downstream effectors, as determined by phosphoprotein array. Combining ganetespib with BGJ398 increased tumor regression 3-fold compared to monotherapy.

Conclusions: The Hsp90 inhibitor ganetespib elicits the rapid degradation of FGFR3 mutants and fusion proteins in bladder cancer cells resulting in tumor regression in animal models, which could be further enhanced by combination with an FGFR inhibitor. These results may provide a framework for the future treatment of FGFR3-dependent bladder cancer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C130.

Citation Format: Jaime L. Acquaviva, Chaohua Zhang, Suqin He, John-Paul Jimenez, Masa Nagai, Jim Sang, Manuel Sequeira, Donald L. Smith, Margaret A. Knowles, David A. Proia. The Hsp90 inhibitor ganetespib promotes the degradation of FGFR3 in bladder cancer models and induces regression in tumors harboring oncogenic FGFR3 fusions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C130.