Targeting FGF2 expression against chemoresistance in colorectal cancer (CRC) cell lines - a potential prognostic biomarker in patients with metastatic colorectal cancer (mCRC) treated with FUFIRI or mIrOx (FIRE1)

Background

Our aim was to evaluate fibroblast growth factor 2 (FGF2) expression in cultivated CRC cell lines exposed to 5-fluorouracil (5-FU) and validate results with clinical data from mCRC patients receiving first-line chemotherapy.

Methods

5-FU IC₅₀ was determined in CRC cell lines DLD1, LoVo, and HCT-15 applying MTT assays. mRNA expression of FGF2 was measured by RT-qPCR with HPRT as reference gene. Threshold values were determined by minimum p-value method. FGF2 expression was knocked down by sh (short hairpin) RNA in vitro. FGF receptor (FGF-R) was inhibited using Dovitinib with DMSO as control. In vitro results were were translated on the randomized FIRE1 trial (5-FU/LV/irinotecan [FUFIRI] vs. irinotecan/oxaliplatin [mIrOx] using Nanostring technology. 187 patients were included in this analysis.

Results

48 h incubation of CRC cell lines with 5-FU showed an increase of FGF2 expression [DLD1: 1.98-fold, p 

Conclusions

FGF2 expression might reflect chemoresistance in CRC cell lines as a knockdown of FGF2 led to a decrease of IC₅₀ for 5-FU in vitro. In FIRE1, high FGF2 expression was associated with lower response rate and overall survival significantly. Interfering the FGF2 system might be a modulator for acquired chemoresistance.

Clinical trial identification

Legal entity responsible for the study

Department of Medicine III, University of Munich; Institute of Pathology, University of Munich

Funding

Weigand-Bohnewand-Gravenhorst-Fond, University of Munich

Disclosure

All authors have declared no conflicts of interest.