Inhibition of the receptor tyrosine kinase AXL restores paclitaxel chemosensitivity in uterine serous cancer

Marguerite L. Palisoul, Jeanne M. Quinn, Emily Schepers, Ian S. Hagemann, Lei Guo, Kelsey Reger, Andrea R. Hagemann, Carolyn K. McCourt, Premal H. Thaker, Matthew A. Powell, David G. Mutch, Katherine C. Fuh

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)2881-2891
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number12
DOIs
StatePublished - Dec 2017

Fingerprint Dive into the research topics of 'Inhibition of the receptor tyrosine kinase AXL restores paclitaxel chemosensitivity in uterine serous cancer'. Together they form a unique fingerprint.

Cite this