Adrenomedullin blockade suppresses sunitinib-resistant renal cell carcinoma growth by targeting the ERK/MAPK pathway

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.

G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS‑MAPK axis pathway

“…The MAPK signaling pathway is largely implicated in the progression and metastasis of various types of cancer, including RCC (54,55). The p38/MAPK, ERK/MAPK and JNK/MAPK cascades are commonly involved in the malignant progression of RCC (56,57). In addition, previous studies reported an association between increased expression of MMPs and activation of the MAPK signaling pathway (37,58), and between ROS overproduction and activation of the MAPK signaling pathway (22,24).…”

Early and late effects of pharmacological ALK inhibition on the neuroblastoma transcriptome

“…In addition to ADM activation upon hypoxia [ 45 – 51 ], ADM was also shown to act as growth factor, prevent apoptosis-mediated cell death, increase tumour cell motility and metastasis and induce angiogenesis in various cancer types [ 47 – 49 , 51 , 53 – 59 ]. Of further importance, it has been reported that hypoxia, which can activate ADM [ 45 – 51 ], induces resistance to ALK inhibitors in non-small cell lung cancer [ 60 ] and that ADM expression levels are increased in tyrosine kinase inhibitor sunitinib resistant renal cell carcinoma [ 61 ]. In view of these observations, we evaluated whether combining an adrenomedullin receptor antagonist (ADM22-52) [ 61 ] together with TAE684 would sensitize NB cells to ALK inhibition.…”

“…Of further importance, it has been reported that hypoxia, which can activate ADM [ 45 – 51 ], induces resistance to ALK inhibitors in non-small cell lung cancer [ 60 ] and that ADM expression levels are increased in tyrosine kinase inhibitor sunitinib resistant renal cell carcinoma [ 61 ]. In view of these observations, we evaluated whether combining an adrenomedullin receptor antagonist (ADM22-52) [ 61 ] together with TAE684 would sensitize NB cells to ALK inhibition. No additional effects on decrease in cell viability were observed (data not shown).…”

A five‐gene signature may predict sunitinib sensitivity and serve as prognostic biomarkers for renal cell carcinoma

“…Earlier studies have implicated that activating the ERK/MAPK pathway could promote tamoxifen‐resistance in ER+ breast cancer (Heckler, Thakor, Schafer, & Riggins, ), whereas, blockading the ERK/MAPK pathway suppressed sunitinib‐resistant RCC growth (Gao. et al, ). Therefore, the results of GO analysis indicated several significant biological processes, cellular components and molecular functions which might be related with the initiation and development of sunitinib resistance in RCC.…”