Background/Aims: Resembling a potential therapeutic drug target, fibroblast growth factor receptor 1 (FGFR1) amplification and expression was assessed in 515 human colorectal cancer (CRC) tissue samples, lymph node metastases and CRC cell lines. Methods: FGFR1 amplification status was determined using fluorescence in situ hybridization. Additionally, we assessed protein levels employing Western blots and immunohistochemistry. The FGFR1 mRNA localization was analyzed using mRNA in situ hybridization. Functional studies employed the FGFR inhibitor NVP-BGJ398. Results: Of 454 primary CRCs, 24 displayed FGFR1 amplification. 92/94 lymph node metastases presented the same amplification status as the primary tumor. Of 99 investigated tumors, 18 revealed membranous activated pFGFR1 protein. FGFR1 mRNA levels were independent of the amplification status or pFGFR1 protein occurrence. In vitro, a strong antiproliferative effect of NVP-BGJ398 could be detected in cell lines exhibiting high FGFR1 protein. Conclusion: FGFR1 is a potential therapeutic target in a subset of CRC. FGFR1 protein is likely to represent a central factor limiting the efficacy of FGFR inhibitors. The lack of correlation between its evaluation at genetic/mRNA level and its protein occurrence indicates that the assessment of the receptor at an immunohistochemical level most likely represents a suitable way to assess FGFR1 as a predictive biomarker for patient selection in future clinical trials.

Weiss J, Sos ML, Seidel D, Peifer M, Zander T, Heuckmann JM, Ullrich RT, Menon R, Maier S, Soltermann A, et al: Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010;2:62ra93.
Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H, et al: Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 2011;6:e20351.
Liang G, Liu Z, Wu J, Cai Y, Li X: Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol Sci 2012;33:531-541.
Powers CJ, McLeskey SW, Wellstein A: Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000;7:165-197.
Wesche J, Haglund K, Haugsten EM: Fibroblast growth factors and their receptors in cancer. Biochem J 2011;437:199-213.
Nakao K, Mehta KR, Fridlyand J, Moore DH, Jain AN, Lafuente A, Wiencke JW, Terdiman JP, Waldman FM: High-resolution analysis of DNA copy number alterations in colorectal cancer by array-based comparative genomic hybridization. Carcinogenesis 2004;25:1345-1357.
Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al: The landscape of somatic copy-number alteration across human cancers. Nature 2010;463:899-905.
Knights V, Cook SJ: De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol Ther 2010;125:105-117.
Perner S, Wagner PL, Soltermann A, LaFargue C, Tischler V, Weir BA, Weder W, Meyerson M, Giordano TJ, Moch H, et al: TTF1 expression in non-small cell lung carcinoma: association with TTF1 gene amplification and improved survival. J Pathol 2009;217:65-72.
Goeke F, Franzen A, Menon R, Goltz D, Kirsten R, Boehm D, Vogel W, Goeke A, Scheble V, Ellinger J, et al: Rationale for treatment of metastatic squamous cell carcinoma of the lung using FGFR inhibitors. Chest 2012;142:1020-1026.
Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, et al: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-1110.
Ney JT, Froehner S, Roesler A, Buettner R, Merkelbach-Bruse S: High-resolution melting analysis as a sensitive prescreening diagnostic tool to detect KRAS, BRAF, PIK3CA, and AKT1 mutations in formalin-fixed, paraffin-embedded tissues. Arch Pathol Lab Med 2012;136:983-992.
Lankat-Buttgereit B, Muller S, Schmidt H, Parhofer KG, Gress TM, Goke R: Knockdown of Pdcd4 results in induction of proprotein convertase 1/3 and potent secretion of chromogranin A and secretogranin II in a neuroendocrine cell line. Biol Cell 2008;100:703-715.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al: The genomic landscapes of human breast and colorectal cancers. Science 2007;318:1108-1113.
Lao VV, Grady WM: Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 2011;8:686-700.
Goel A, Boland CR: Epigenetics of colorectal cancer. Gastroenterology 2012;143:1442-1460.
Bandres E, Agirre X, Bitarte N, Ramirez N, Zarate R, Roman-Gomez J, Prosper F, Garcia-Foncillas J: Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer 2009;125:2737-2743.
Guagnano V, Kauffmann A, Wohrle S, Stamm C, Ito M, Barys L, Pornon A, Yao Y, Li F, Zhang Y, et al: FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012;2:1118-1133.
Arrington AK, Heinrich EL, Lee W, Duldulao M, Patel S, Sanchez J, Garcia-Aguilar J, Kim J: Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int J Mol Sci 2012;13:12153-12168.
Stachowiak MK, Fang X, Myers JM, Dunham SM, Berezney R, Maher PA, Stachowiak EK: Integrative nuclear FGFR1 signaling (INFS) as a part of a universal ‘feed-forward-and-gate' signaling module that controls cell growth and differentiation. J Cell Biochem 2003;90:662-691.
Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C, Schmid H, et al: Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-[6-(4-ethyl-piperazin-1-yl)phenylamino-pyrimidin-4-yl]-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 2011;54:7066-7083.
Kriegl L, Jung A, Engel J, Jackstadt R, Gerbes AL, Gallmeier E, Reiche JA, Hermeking H, Rizzani A, Bruns CJ, et al: Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res 2010;16:5529-5538.
Peng H, Myers J, Fang X, Stachowiak EK, Maher PA, Martins GG, Popescu G, Berezney R, Stachowiak MK: Integrative nuclear FGFR1 signaling (INFS) pathway mediates activation of the tyrosine hydroxylase gene by angiotensin II, depolarization and protein kinase C. J Neurochem 2002;81:506-524.
Wong A, Lamothe B, Lee A, Schlessinger J, Lax I: FRS2-α attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proc Natl Acad Sci USA 2002;99:6684-6689.
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