Fibroblast growth factor receptor 4 induced resistance to radiation therapy in colorectal cancer

Mohamed A. Ahmed; Edgar Selzer; Wolfgang Dörr; Gerd Jomrich; Felix Harpain; Gerd R. Silberhumer; Leonhard Müllauer; Klaus Holzmann; Bettina Grasl-Kraupp; Michael Grusch; Walter Berger; Brigitte Marian

doi:10.18632/oncotarget.12099

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This article has been corrected. Correction in: Oncotarget. 2019; 10:5385-5386.

Fibroblast growth factor receptor 4 induced resistance to radiation therapy in colorectal cancer

Mohamed A. Ahmed, Edgar Selzer, Wolfgang Dörr, Gerd Jomrich, Felix Harpain, Gerd R. Silberhumer, Leonhard Müllauer, Klaus Holzmann, Bettina Grasl-Kraupp, Michael Grusch, Walter Berger and Brigitte Marian _

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Oncotarget. 2016; 7:69976-69990. https://doi.org/10.18632/oncotarget.12099

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Abstract

Mohamed A. Ahmed1,2, Edgar Selzer3, Wolfgang Dörr3,4, Gerd Jomrich5, Felix Harpain5, Gerd R. Silberhumer5, Leonhard Müllauer6, Klaus Holzmann1, Bettina Grasl-Kraupp1, Michael Grusch1, Walter Berger1, Brigitte Marian1

1Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria

2Radiation Biology Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Egypt

3Department of Radiotherapy and Radiobiology, Medical University of Vienna, Austria

4Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria

5Department of Surgery, Medical University Vienna, Austria

6Clinical Institute of Pathology, Medical University Vienna, Austria

Correspondence to:

Brigitte Marian, email: [email protected]

Keywords: FGFR4, colorectal cancer, radiotherapy, RAD51

Received: February 08, 2016 Accepted: September 12, 2016 Published: September 17, 2016

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.

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Fibroblast growth factor receptor 4 induced resistance to radiation therapy in colorectal cancer

Abstract