Abstract B036: Targeting Hsp90-Cdc37 complex in glioma harboring FGFR3-TACC3

Abstract

Abstract Glioblastoma is one of the most lethal central nervous system tumors with the poorest prognosis. Fusion genes are common chromosomal aberrations in malignancies that can be used as prognostic markers as well as drug targets in clinical practice. The FGFR3-TACC3 (F3T3) fusion gene was discovered in glioblastoma, with an occurrence rate of up to 8.3% and leading to uncontrolled proliferation and chromosomal instability. Our previous study has shown that F3T3, generated by a rearrangement of chromosome, led to the loss of the 3′-UTR of FGFR3, blocking epigenetic regulation of miR-99a and enhancing expression of the fusion gene. To further explore whether there is a post-translational regulation on F3T3 protein, we immunoprecipitated (IP) the proteins that interact with F3T3 in U251 glioblastoma cells overexpressing the F3T3 or wild-type FGFR3, followed by LC-MS/MS analyses. Quantitative proteomic analysis suggest a stronger interactions of the F3T3 fusion protein with Hsp90 and Cdc37 proteins when compared with wild-type FGFR3. To test inhibition of F3T3 association with the Hsp90-Cdc37 complex, we treated U251 and LN229 cells constitutively expressing F3T3 with either Hsp90 inhibitors or siRNA of Cdc37. Targeting Hsp90-Cdc37 complex significantly suppressed the activation of F3T3 and downstream signaling pathways. Intriguingly, both Hsp90 and Cdc37 inhibition caused a degradation of glycosylation form of F3T3 protein. F3T3 was found highly expressed in both the untreated and matched recurrence glioblastoma, indicating a resistance to the concurrent radiotherapy and temozolomide (TMZ) treatment. Our results provide evidence that the F3T3 fusion gene confers drug resistance to TMZ induced DNA damage and using Hsp90 inhibitor chemosensitizes F3T3 glioma cells to TMZ. In conlusion, our findings establish that F3T3 is an strong Hsp90 client that shows strong addiction to the Hsp90-Cdc37 complex and suggests a novel strategy for targeting F3T3 fusion gene in glioma. Citation Format: Tao Li, Farideh Mehraein-Ghomi, Sanjeev V. Namjoshi, Qian Qian Song, Elizabeth A. Ballard, Mary E. Forbes, Ping-Chieh Chou, Xuejun Yang, Wei Zhang. Targeting Hsp90-Cdc37 complex in glioma harboring FGFR3-TACC3 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B036. doi:10.1158/1535-7163.TARG-19-B036