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Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

Zhou, L ; Liu, X-D ; Sun, M ; Zhang, X ; German, P ; Bai, S ; Ding, Z ; Tannir, N ; Wood, C G ; Matin, S F ; Karam, J A ; Tamboli, P ; Sircar, K ; Rao, P ; Rankin, E B ; Laird, D A ; Hoang, A G ; Walker, C L ; Giaccia, A J ; Jonasch, E

Oncogene, 2016-05, Vol.35 (21), p.2687-2697 [Periódico revisado por pares]

England: Nature Publishing Group

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Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma
Autor: Zhou, L ; Liu, X-D ; Sun, M ; Zhang, X ; German, P ; Bai, S ; Ding, Z ; Tannir, N ; Wood, C G ; Matin, S F ; Karam, J A ; Tamboli, P ; Sircar, K ; Rao, P ; Rankin, E B ; Laird, D A ; Hoang, A G ; Walker, C L ; Giaccia, A J ; Jonasch, E
Assuntos: Angiogenesis ; Angiogenesis Inhibitors - pharmacology ; Animal models ; Animals ; Axl protein ; Cancer therapies ; Carcinoma, Renal cell ; Carcinoma, Renal Cell - drug therapy ; Carcinoma, Renal Cell - enzymology ; Carcinoma, Renal Cell - pathology ; Cell culture ; Cell migration ; Cell Proliferation - drug effects ; Cell receptors ; Development and progression ; DNA microarrays ; Drug resistance ; Drug Resistance, Neoplasm ; Drug therapy ; Endothelial cells ; Gene expression ; Genetic aspects ; Health aspects ; Humans ; Indoles - pharmacology ; Innovations ; Kidney cancer ; Kidney Neoplasms - drug therapy ; Kidney Neoplasms - enzymology ; Kidney Neoplasms - pathology ; Kinases ; Mesenchyme ; Metastases ; Metastasis ; Methods ; Mice ; Mice, Nude ; Molecular Targeted Therapy ; Patient outcomes ; Patients ; Phosphotransferases ; Properties ; Proto-Oncogene Proteins - antagonists & inhibitors ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-met - antagonists & inhibitors ; Proto-Oncogene Proteins c-met - genetics ; Proto-Oncogene Proteins c-met - metabolism ; Pyrroles - pharmacology ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Renal cell carcinoma ; Signal Transduction ; Sunitinib ; Tumors ; Tyrosine ; Umbilical vein ; Vascular endothelial growth factor ; Xenograft Model Antitumor Assays ; Xenografts ; β-Catenin
É parte de: Oncogene, 2016-05, Vol.35 (21), p.2687-2697
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Descrição: Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

Zhou, L ; Liu, X-D ; Sun, M ; Zhang, X ; German, P ; Bai, S ; Ding, Z ; Tannir, N ; Wood, C G ; Matin, S F ; Karam, J A ; Tamboli, P ; Sircar, K ; Rao, P ; Rankin, E B ; Laird, D A ; Hoang, A G ; Walker, C L ; Giaccia, A J ; Jonasch, E

England: Nature Publishing Group

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