title: Fibroblast growth factor receptor 4 induced resistance to radiation therapy in colorectal cancer.
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.
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.|Radiation Biology Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ahmed
authors.affiliation: Department of Radiotherapy and Radiobiology, Medical University of Vienna, Austria.
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
authors.affiliation: Department of Radiotherapy and Radiobiology, Medical University of Vienna, Austria.|Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dörr
authors.affiliation: Department of Surgery, Medical University Vienna, Austria.
authors.forename: Gerd
authors.initials: G
authors.lastname: Jomrich
authors.affiliation: Department of Surgery, Medical University Vienna, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Harpain
authors.affiliation: Department of Surgery, Medical University Vienna, Austria.
authors.forename: Gerd R
authors.initials: GR
authors.lastname: Silberhumer
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Austria.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059186:Chemoradiotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D004260:DNA Repair; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D051135:Rad51 Recombinase / Q000502:physiology; D011836:Radiation Tolerance; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000502:physiology*
chemical_list: C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D051135:Rad51 Recombinase
keywords: FGFR4; RAD51; colorectal cancer; radiotherapy