Abstract
BackgroundWe 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.MethodsEffects 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.ResultsIn 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.ConclusionsAmong 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-2000-8) contains supplementary material, which is available to authorized users.
Highlights
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
Anti-tumor activity in vitro All four FGFRs were detected by qPCR in all CRC cell lines in vitro (Fig. 1a)
In our study we focused only on CRC cell lines and not on other tumor types, such as endometrial, gastric and breast cancer, were deregulation of the FGFR pathway has been shown to be implicated in cancer [3]
Summary
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. The standard treatment for patients with rectal cancer is chemoradiotherapy followed by surgery, but 30 % of these patients develop local and distant recurrences [1]. Fibroblast growth factors (FGFs) and their receptors are recognized oncogenes. Dysregulated expression of many FGFs and all four FGFRs has been reported in CRC, especially for FGFR2 [5,6,7,8,9,10,11]. The effectiveness of FGFR2-targeting therapy for CRC has been demonstrated in vitro and in vivo illustrating the potential of FGFR2 as novel molecular target for CRC [7]
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