Expression of fibroblast growth factor receptors (FGFRs) in atypical teratoid rhabdoid tumor (ATRT)
Atypical teratoid rhabdoid tumors (ATRT) are rare aggressive malignant tumors of the central nervous system, typically found in the cerebellum or brain stem of children three years of age and younger. ATRT is difficult to diagnose and treat, with only 10% of approximately 200 cases in the United States each year ending in survival. These tumors are traditionally characterized by the loss or mutation of the tumor suppressor gene SMARCB1/INI1. Fibroblast Growth Factor Receptors (FGFRs) have recently been found to be overexpressed in similar malignant rhabdoid tumors (MRT). FGFRs are involved in proliferation, differentiation, apoptosis, and migration. We hypothesize that FGFRs may play an important role in ATRT. Using RT-PCR, qRT-PCR, and western blot analyses, we evaluated the expression of FGFRs in seven ATRT cell lines as well as four control lines. RT-PCR analysis showed expression of either FGFR1, FGFR2 or FGFR3 in a majority of the ATRT cell lines (6/7), including several lines that expressed more than one FGFR. Similarly, qRT-PCR analysis showed robust expression of FGFR1, FGFR2, and FGFR3 in CHLA-04-ATRT and FGFR3 in CHLA-02-ATRT. Western blots analysis showed FGFR1 protein expression in CHLA-04-ATRT, CHLA-05-ATRT, and CHLA-266 cells; and FGFR2 protein was seen in CHLA-04-ATRT and CHLA-266. Furthermore, drug dose response assays (DDR) were conducted to determine the activity of FGFR inhibitors on ATRT cell growth. ATRT cells were treated with FGFR inhibitors BGJ-398 and AZD-4547. Calculated IC50 values showed varying responses to the inhibitors with CHLA-04-ATRT cells being 400x and 200x more sensitive to BGJ-398 and AZD-4547 respectively than the least sensitive cell line CHLA-06-ATRT. This correlates with our earlier finding that CHLA-04-ATRT expresses both FGFR1 and FGFR2 while CHLA-06-ATRT did not. Our findings indicate that FGFRs may be important targets in ATRT and FGFR inhibitors could be used as therapeutics in treatment of ATRT in children.