Faculty, Staff and Student Publications
Publication Date
4-6-2022
Journal
Molecular Therapy
Abstract
The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated F3-T3, and thereby suppresses F3-T3 oncogenic activity. Gliomas harboring F3-T3 are resistant to TMZ chemotherapy. HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via the inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chaperone system and suggests a new clinical option for targeting this genetic aberration in cancer.
Keywords
Carcinogenesis, Cell Cycle Proteins, Cell Line, Tumor, Chaperonins, Glioblastoma, Glioma, HSP90 Heat-Shock Proteins, Humans, Microtubule-Associated Proteins, Molecular Chaperones, Neoplasm Recurrence, Local, Receptor, Fibroblast Growth Factor, Type 3, Temozolomide, FGFR3-TACC3, glioma, HSP90, CDC37, glycosylation, TMZ resistance
DOI
10.1016/j.ymthe.2022.02.009
PMID
35151844
PMCID
PMC9077375
PubMedCentral® Posted Date
2-10-2022
PubMedCentral® Full Text Version
Post-print
Graphical Abstract
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons