title: In vitro and in vivo evaluation of the radiosensitizing effect of a selective FGFR inhibitor (JNJ-42756493) for rectal cancer.
abstract: BACKGROUND
  We examined the anti-tumor effect and radiosensitizing potential of a small molecule inhibitor of fibroblast growth factor receptor (FGFR) in colorectal cancer (CRC) in vitro and in vivo.
  
  
  METHODS
  Effects of in vitro drug treatment on cell survival, proliferation, FGFR signaling, cell cycle distribution, apoptosis and radiosensitivity were assessed using various CRC cell lines with FGFR wild type (Caco2 and HCA7) and FGFR2 amplification (HCT116, NCI-H716). In vivo tumor responses to FGFR inhibition with and without radiation therapy were evaluated by growth delay assays in two colorectal xenograft mouse models (NMRI nu/nu mice injected with NCI-H716 or CaCo2 cells). Mechanistic studies were conducted using Western blot analysis, immunohistochemistry and qPCR.
  
  
  RESULTS
  In the tested cell lines, the FGFR inhibitor (JNJ-42756493) was effective in vitro and in vivo in CRC tumors with highest expression of FGFR2 (NCI-H716). In vitro, cell proliferation in this line was decreased, associated with increased apoptotic death and decreased cell survival. In vivo, growth of NCI-H716 tumors was delayed by 5 days by drug treatment alone, although when drug delivery was stopped the relative tumor volume increased compared to control. The FGFR inhibitor did not radiosensitize NCI-H716 tumors either in vitro or in vivo.
  
  
  CONCLUSIONS
  Among tested CRC cell lines, the growth inhibitory activity of this FGFR inhibitor was evident in cell lines with high constitutive FGFR2 expression, suggesting that FGFR addiction may provide a window for therapeutic intervention, though caution is advised. Preclinical study with NCI-H716 and Caco2 tumor demonstrated that continued presence of drug could be essential for tumor growth control, especially in cells with aberrant FGFR expression. In the tested set-up, the inhibitor showed no radiosensitizing effect.
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. maud.verstraete@med.kuleuven.be.
authors.forename: Maud
authors.initials: M
authors.lastname: Verstraete
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. Annelies.debucquoy@med.kuleuven.be.
authors.forename: Annelies
authors.initials: A
authors.lastname: Debucquoy
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. annelies.gonnissen@med.kuleuven.be.
authors.forename: Annelies
authors.initials: A
authors.lastname: Gonnissen
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. ruveyda.dok@med.kuleuven.be.
authors.forename: Ruveyda
authors.initials: R
authors.lastname: Dok
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. sofie.isebaert@med.kuleuven.be.
authors.forename: Sofie
authors.initials: S
authors.lastname: Isebaert
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. ellen.devos@med.kuleuven.be.
authors.forename: Ellen
authors.initials: E
authors.lastname: Devos
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine, UCLA, 200 UCLA Medical Plaza, Suite B265, Los Angeles, CA, 90095-6951, USA. WMcBride@mednet.ucla.edu.
authors.forename: William
authors.initials: W
authors.lastname: McBride
authors.affiliation: Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. karin.haustermans@uzleuven.be.|Radiation Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. karin.haustermans@uzleuven.be.
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011810:Quinoxalines; D011838:Radiation-Sensitizing Agents; C000604580:erdafitinib; D051497:Receptor, Fibroblast Growth Factor, Type 2