Abstract
In colorectal cancer (CRC), fibroblast growth factor receptor 4 (FGFR4) is upregulated and acts as an oncogene. This study investigated the impact of this receptor on the response to neoadjuvant radiotherapy by analyzing its levels in rectal tumors of patients with different responses to the therapy. Cellular mechanisms of FGFR4-induced radioresistance were analyzed by silencing or over-expressing FGFR4 in CRC cell line models. Our findings showed that the FGFR4 staining score was significantly higher in pre-treatment biopsies of non-responsive than responsive patients. Similarly, high expression of FGFR4 inhibited radiation response in cell line models. Silencing or inhibition of FGFR4 resulted in a reduction of RAD51 levels and decreased survival in radioresistant HT29 cells. Increased RAD51 expression rescued cells in the siFGFR4-group. In radiosensitive SW480 and DLD1 cells, enforced expression of FGFR4 stabilized RAD51 protein levels resulting in enhanced clearance of γ-H2AX foci and increased cell survival in the mismatch repair (MMR)-proficient SW480 cells. MMR-deficient DLD1 cells are defective in homologous recombination repair and no FGFR4-induced radioresistance was observed. Based on our results, FGFR4 may serve as a predictive marker to select CRC patients with MMR-proficient tumors who may benefit from pre-operative radiotherapy.
Highlights
Despite technical and therapeutic improvements in recent years, colorectal cancer (CRC) remains one of the most deadly cancers worldwide, in both men and women
Our findings indicate that targeting fibroblast growth factor receptor 4 (FGFR4) induces radiosensitization that is associated with the attenuation of double strand breaks (DSBs) repair by RAD51-mediated homologous recombination
In DLD1 cells the persisting radiation-induced γ-H2AX foci were not reduced (Figure 8F). This was further confirmed by the significant enhancement of the homologous recombination (HR)-repair capacity, which was exclusively observed in SW480 cells (Figure 8G, p = 0.0002), but not DLD1 cells (Figure 8H, p = 0.6), upon increased FGFR4 expression
Summary
Despite technical and therapeutic improvements in recent years, colorectal cancer (CRC) remains one of the most deadly cancers worldwide, in both men and women. Increased FGFR expression and/or activity has been reported to play a role in treatment resistance towards both conventional and EGFR-targeting strategies [14,15,16]. Li et al [19] showed a correlation between high FGFR2 expression and poor therapeutic response to neoadjuvant chemoradiation. FGFR4 silencing resulted in decreased activity of pro-survival signaling, expression of the anti-apoptotic proteins, and showed synergistic interaction with 5-fluorouracil (5-FU) and oxaliplatin in colon cancer cell lines [22]. We investigated for the first time the role of FGFR4 in the resistance of colorectal cancer cells to radiotherapy, and the possible mechanisms of interaction with the DNA damage response machinery (DDR). Our findings indicate that targeting FGFR4 induces radiosensitization that is associated with the attenuation of DSB repair by RAD51-mediated homologous recombination
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