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The combination of gemcitabine plus an anti-FGFR inhibitor can have a synergistic antitumor effect on FGF-activating cholangiocarcinoma.
- Source :
-
Cancer letters [Cancer Lett] 2024 Jul 28; Vol. 595, pp. 216997. Date of Electronic Publication: 2024 May 25. - Publication Year :
- 2024
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Abstract
- Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50 = 19.3, 22.6 mg/dl, p = 0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50 = 7.18,7.60 nM, p = 0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Cell Proliferation drug effects
Mice, Nude
Signal Transduction drug effects
Fibroblast Growth Factors metabolism
Fibroblast Growth Factors genetics
Receptors, Fibroblast Growth Factor antagonists & inhibitors
Receptors, Fibroblast Growth Factor metabolism
Drug Resistance, Neoplasm drug effects
Protein Kinase Inhibitors pharmacology
Mutation
Apoptosis drug effects
Morpholines
Pyrroles
Gemcitabine
Cholangiocarcinoma drug therapy
Cholangiocarcinoma pathology
Cholangiocarcinoma genetics
Deoxycytidine analogs & derivatives
Deoxycytidine pharmacology
Deoxycytidine administration & dosage
Drug Synergism
Bile Duct Neoplasms drug therapy
Bile Duct Neoplasms pathology
Bile Duct Neoplasms genetics
Antineoplastic Combined Chemotherapy Protocols pharmacology
Xenograft Model Antitumor Assays
Pyrimidines pharmacology
Pyrimidines administration & dosage
Receptor, Fibroblast Growth Factor, Type 2 antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 metabolism
Receptor, Fibroblast Growth Factor, Type 2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 595
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 38801887
- Full Text :
- https://doi.org/10.1016/j.canlet.2024.216997