Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer
| Autor: | Katherine Fuh, Hollie Beck-Noia, David G. Mutch, M. Palisoul, Lei Guo, J.M. Quinn, Andrea R. Hagemann, Premal H. Thaker, Peinan Zhao, M. Greenwade, Carolyn K. McCourt, Gregory Opara, Matthew A. Powell, Katina Massad, Ian S. Hagemann |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Paclitaxel Cell Survival medicine.medical_treatment Article Receptor tyrosine kinase Carboplatin Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Cell Proliferation Ovarian Neoplasms Chemotherapy Tissue microarray Taxane biology business.industry Receptor Protein-Tyrosine Kinases Cancer Drug Synergism Triazoles medicine.disease Xenograft Model Antitumor Assays Axl Receptor Tyrosine Kinase Up-Regulation Gene Expression Regulation Neoplastic Benzocycloheptenes 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein Cancer research Female Ovarian cancer business |
| Zdroj: | Molecular Cancer Therapeutics. 18:389-398 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-18-0537 |
| Popis: | Ovarian cancer, one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to first-line platinum and taxane therapy in ovarian cancer. AXL staining was quantified in a patient tissue microarray and correlated with chemoresponse of patients. We used small hairpin RNAs to knock down AXL expression and the small-molecule inhibitor BGB324 to inhibit AXL and assessed sensitivity of cell lines and primary patient-derived cells to chemotherapy. We quantified platinum accumulation by inductivity-coupled plasma phase mass spectrometry. Finally, we treated chemoresistant patient-derived xenografts with chemotherapy, BGB324, or chemotherapy plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant patient tumors and cell lines than in chemosensitive tumors and cell lines. AXL staining significantly predicted chemoresponse. Knockdown and inhibition of AXL dose-dependently improved response to paclitaxel and carboplatin in both cell lines and primary cells. AXL inhibition increased platinum accumulation by 2-fold (*, P < 0.05). In vivo studies indicated that AXL inhibition enhanced the ability of chemotherapy to prevent tumor growth (****, P < 0.0001). AXL contributes to platinum and taxane resistance in ovarian cancer, and inhibition of AXL improves chemoresponse and accumulation of chemotherapy drugs. This study supports continued investigation into AXL as a clinical target. |
| Databáze: | OpenAIRE |
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