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Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2017 Dec; Vol. 16 (12), pp. 2881-2891. Date of Electronic Publication: 2017 Sep 13. - Publication Year :
- 2017
-
Abstract
- Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo We used short hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition (EMT) in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the EMT in vitro Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared with no treatment or single-agent treatments ( P < 0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC. Mol Cancer Ther; 16(12); 2881-91. ©2017 AACR .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Benzocycloheptenes administration & dosage
Cell Proliferation drug effects
Drug Synergism
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Paclitaxel administration & dosage
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins metabolism
Receptor Protein-Tyrosine Kinases metabolism
Triazoles administration & dosage
Uterine Neoplasms pathology
Xenograft Model Antitumor Assays
Axl Receptor Tyrosine Kinase
Antineoplastic Combined Chemotherapy Protocols pharmacology
Benzocycloheptenes pharmacology
Paclitaxel pharmacology
Proto-Oncogene Proteins antagonists & inhibitors
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Triazoles pharmacology
Uterine Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 16
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 28904132
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-17-0587