title: FGFR2 is amplified in the NCI-H716 colorectal cancer cell line and is required for growth and survival.
abstract: Aberrant kinase activation resulting from mutation, amplification, or translocation can drive growth and survival in a subset of human cancer. FGFR2 is amplified in breast and gastric cancer, and we report here the first characterization of FGFR2 gene amplification in colorectal cancer in the NCI-H716 colorectal cancer cell line. FGFR2 is highly expressed and activated in NCI-H716 cells, and FGFR selective small molecule inhibitors or FGFR2 shRNA strongly inhibited cell viability in vitro, indicating "addiction" of NCI-H716 cells to FGFR2. NCI-H716 growth in a xenograft model was also inhibited by an FGFR small molecule inhibitor. FGFR2 was required for activation of multiple downstream signaling proteins including AKT, ERK, S6RP and NFKB. Inhibition of downstream kinases such as AKT or ERK alone had modest effects on proliferation, whereas combined inhibition of AKT and ERK signaling resulted in a loss of viability similar to FGFR2 inhibition. We identified elevated FGFR2 expression in a small subset of primary colorectal cancer, however FGFR2 amplification was not observed. Although FGFR2 amplification is not common in primary colon cancer or lymph node and liver metastases, other subsets of colorectal cancer such as ascites, from which the NCI-H716 cell line was derived, have yet to be tested. These results suggest that emerging FGFR inhibitor therapeutics may have efficacy in a subset of colon cancer driven by FGFR2 amplification.
authors: Merck Research Labs, Boston, Massachusetts, United States of America.
authors: Anjili
authors: A
authors: Mathur
authors: Merck Research Labs, Boston, Massachusetts, United States of America.
authors: Christopher
authors: C
authors: Ware
authors: Merck Research Labs, Boston, Massachusetts, United States of America.
authors: Lenora
authors: L
authors: Davis
authors: Hamon Center for Therapeutic Oncology, University of Texas Southwestern, Dallas, Texas, United States of America.
authors: Adi
authors: A
authors: Gazdar
authors: Merck Research Labs, Boston, Massachusetts, United States of America.
authors: Bo-Sheng
authors: BS
authors: Pan
authors: Merck Research Labs, Boston, Massachusetts, United States of America.
authors: Bart
authors: B
authors: Lutterbach
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; C115711:PD 173074; D011743:Pyrimidines; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases