Abstract
PurposeTo evaluate the mechanisms underlying sunitinib resistance in RCC and to identify targets that may be used to overcome this resistance.ResultsReanalysis of transcriptome microarray datasets (GSE64052 and GSE76068) showed that adrenomedullin expression was increased in sunitinib-resistant tumors. And adrenomedullin expression was increased in sunitinib-resistant tumor xenografts, accompanied by upregulation of phospho-ERK levels. However, blocking adrenomedullin inhibited sunitinib-resistant tumor growth. Treatment of RCC cells with sunitinib and ADM22-52 was superior to monotherapy with either agent. Additionally, adrenomedullin upregulated cAMP and activated the ERK/MAPK pathway, promoting cell proliferation, while knockdown of adrenomedullin inhibited RCC cell growth and invasion in vitro.Materials and methodsWe searched the Gene Expression Omnibus (GEO) database to find data regarding sunitinib-resistant RCC. These data were subsequently reanalyzed to identify targets that contribute to sunitinib resistance, and adrenomedullin upregulation was found to mediate sunitinib resistance in RCC. Then, we created an RCC mouse xenograft model. Mice were treated with sunitinib, an adrenomedullin receptor antagonist (ADM22-52), a MEK inhibitor (PD98059) and different combinations of these three drugs to investigate their effects on tumor growth. RCC cells (786-0) were cultured in vitro and treated with an ADM22-52 or PD98059 to determine whether adrenomedullin activates the ERK/MAPK pathway. Adrenomedullin was knocked down in 786-0 cells via siRNA, and the effects of this knockdown on cell were subsequently investigated.ConclusionsAdrenomedullin plays an important role in RCC resistance to sunitinib treatment. The combination of sunitinib and an adrenomedullin receptor antagonist may result in better outcomes in advanced RCC patients.
Highlights
Renal cell carcinoma (RCC) accounts for approximately 2% of adult malignancies worldwide, an incidence that is increasing by 1.5–5.9% per year [1]
Reanalysis of transcriptome microarray datasets (GSE64052 and GSE76068) showed that adrenomedullin expression was increased in sunitinibresistant tumors
Adrenomedullin expression was increased in sunitinib-resistant tumor xenografts, accompanied by upregulation of phospho-ERK levels
Summary
Renal cell carcinoma (RCC) accounts for approximately 2% of adult malignancies worldwide, an incidence that is increasing by 1.5–5.9% per year [1]. RCC tends to be highly vascular; in recent years, angiogenesis inhibitors, including sorafenib and sunitinib, have been used to treat RCC. Both of these agents are receptor tyrosine kinase (RTK) inhibitors and www.impactjournals.com/oncotarget have already been approved for advanced RCC treatment by the FDA [2]. Clinical trial data indicate that both sorafenib and sunitinib are able to improve progressionfree survival and overall survival in RCC patients by targeting the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) [3, 4]
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