In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A24-A24
Kurzfassung:
Fibroblast growth factor receptor 4 (FGFR4) is an attractive target in Oncology. A gene encoding fibroblast growth factor 19 (FGF19), the main ligand of FGFR4, is frequently amplified (A) and/or overexpressed (OE) in human malignancies according to The Cancer Genome Atlas (TCGA) (breast cancer 12.8% A, 0.6% OE; head and neck cancer 20.5% A, 7.1% OE; squamous cell carcinoma of the lung 11.6% A, 11.8% OE; hepatocellular carcinoma (HCC) 4.2% A, 21.1% OE; colorectal carcinoma 0% A, 15.4% OE; pancreatic carcinoma 0% A, 32.1% OE; endometrial carcinoma 0.8% A, 17.7% OE; bladder carcinoma 8.5% A, 1.9% OE). The objective of this study was to identify the hallmarks of FGFR4 pathway dependence in human tumors. LY2874455, a selective SMI with a potent activity against FGFR1, 2, 3 and 4, was tested in vitro using Cancer Cell Line Sensitivity Panel that included 539 histologically and genetically diverse tumor cell lines representing human malignancies. Cell lines that were most sensitive to LY2874455 were enriched for genetic FGFR pathway aberrations including FGF19 amplification. We therefore hypothesized that FGF19 amplification and/or overexpression might be molecular predictors of antitumor efficacy of LY2874455. We further tested LY2874455 in a panel of 14 HCC, 4 colorectal, 4 esophageal, 2 breast, 2 pancreatic and 1 head and neck carcinoma cell lines with FGF19 amplification and/or expression using a cell viability assay. Among all cell lines tested, LY2874455 activity was restricted to HCC cell lines with concurrent FGF19 amplification and expression (IC50 = 0.001-72 nM). It is known that endocrine effects of FGF19 require beta-klotho (KLB), a co-receptor whose expression is restricted to very few cell types including hepatocytes. We thus speculated that KLB expression could underlie FGFR4 pathway dependence in a subset of HCC with FGF19 amplification and/or overexpression. To corroborate this hypothesis, we employed doxycycline-inducible shRNA-mediated KLB knockdown in FGF19-amplified HCC cell lines, and demonstrated that ablated KLB expression decreased sensitivity to LY2874455 in JHH-7 (IC50 shift from 3.9 to 198 nM) and Hep3B (IC50 shift from 0.6 to 18 nM). Furthermore, in Hep3B cells, KLB knockdown was associated with a disrupted downstream signaling as exemplified by abrogated early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog (FOS) expression upon FGF19 stimulation. These results suggest that FGF19 amplification or overexpression per se do not confer tumor cell sensitivity to FGFR blockade. Instead, FGFR4 inhibition seems to be most efficacious in FGF19-amplified tumor cells with concomitant FGF19, FGFR4 and KLB expression. This study established a mechanistic link between KLB expression and FGFR SMI efficacy in the setting of FGF19 amplification and/or overexpression and revealed a molecular profile of HCC patients that may benefit from FGFR inhibitors. Citation Format: Amelie Forest, Sandra Nakasone, Ying Wang, Xuemei Guo, Timothy R. Mack, Genshi Zhao, Yong G. Yue, Xueqian Gong, Trent Stewart, Sean Buchanan, Christoph Reinhard, Ruslan Novosiadly. Beta-klotho expression is associated with the antitumor activity of pan-FGFR inhibitor in human malignancies with FGF19 amplification. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A24.
Materialart:
Online-Ressource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-15-A24
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2015
ZDB Id:
2062135-8
SSG:
12
