Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis.
BACKGROUND
Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI.


METHODS
We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed.


RESULTS
IRI exposure induced expression of FGFR3 as well as its ligands FGF8 and FGF18 both in cell cultures and in xenograft tumors. As overexpression of FGFR3 mitigated IRI-induced apoptosis in CRC cell models, this suggests that the drug itself activated a survival response. On the cellular level, the antiapoptotic protein bcl-xl was upregulated and caspase 3 activation was inhibited. Targeting FGFR3 signaling using a dominant-negative receptor mutant sensitized cells for IRI. In addition, the FGFR inhibitor PD173074 acted synergistically with the chemotherapeutic drug and significantly enhanced IRI-induced caspase 3 activity in vitro. In vivo, PD173074 strongly inhibited growth of IRI-treated tumors.


CONCLUSIONS
Together, our results indicate that targeting FGFR3 can be a promising strategy to enhance IRI response in CRC patients.
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Zeynep N
ZN
Erdem
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Stefanie
S
Schwarz
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Daniel
D
Drev
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Christine
C
Heinzle
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Andrea
A
Reti
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Petra
P
Heffeter
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Xenia
X
Hudec
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Klaus
K
Holzmann
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Bettina
B
Grasl-Kraupp
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Walter
W
Berger
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Michael
M
Grusch
Medical University of Vienna, Department of Medicine 1, Institute of Cancer Research and Comprehensive Cancer Center Vienna, Borschkegasse 8a, 1090 Vienna, Austria. Electronic address: brigitte.marian@meduniwien.ac.at.
Brigitte
B
Marian