MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model

Díaz-Montero, C. Marcela; Mao, Frances; Barnard, John; Parker, Yvonne; Zamanian-Daryoush, Maryam; Pink, John J.; Finke, James H.; Rini, Brian I.; Lindner, Daniel J.

doi:10.1038/bjc.2016.263

Cited by 38 publications

(30 citation statements)

References 39 publications

(42 reference statements)

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“…These findings support the crucial role of mek1 kinase may be useful in cancer cells response to antiangiogenic agents. It was previously reported that inhibition of mek1 in the renal cell carcinoma xenograft model with acquired resistance to sunitinib successfully improved anti-tumor drug efficacy [ 47 ]. Therefore, targeting mek1 may be a promising pathway in treating TKI-resistant papillary renal cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells

et al. 2017

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BackgroundThe aim of this study is to determine the effect of hypoxia on axitinib and sorafenib-treated renal cell carcinoma (RCC) cells. Hypoxia is a crucial factor influencing transcription process via protein modulation, which was shown i.e. in pancreatic cancer. Until now, hypoxia has been defined as associated with poorer outcome and inducing chemotherapy resistance in solid tumors. The unique phenomenon of pseudo-hypoxia connected with vhl mutation was observed in clear-cell, but not in papillary RCC, and the treatment of this subtype of cancer is still challenging. Despite the introduction of new antiangiogenic targeted therapies (inter alia tyrosine kinase inhibitors, TKIs), patients still develop both primary and acquired resistance. Overcoming resistance to TKIs, also in papillary RCC, may be possible by finding significantly modified protein expression. To do this, hypoxic 3D in vitro models must be developed to mimic both molecular pathways typical for low oxygen tension and cell–cell dynamics in tumor-like spatial structures.ResultsClear-cell and papillary renal cell carcinoma (cc and pRCC) cell lines were used in the study to determine the impact of hypoxia on primary drug resistance phenomenon previously observed in papillary, but not in ccRCC. Resistance was confirmed in monolayer culture and in 3D models in soft agar and suspension culture. Human papillary kidney cancer stem-like cells (HKCSCs) cultured in hypoxia developed resistance to sorafenib, while when cultured in normoxia resistance to axitinib has developed. Flow cytometry revealed that hypoxia decreased proliferation rates in all investigated RCC cells. In HKCSCs, there was an increase of quiescent cells (Ki67−) and percentage of cells arrested in S phase. It also appeared that map2k1 and eif4b protein expression is altered in papillary RCC resistant to tested drugs at different oxygen tensions. Also, HKCSCs did not express vegfr-1, braf nor c-kit, TKIs target receptors, which were present in ccRCC cells sensitive to TKI treatment.ConclusionsThe results confirm that low oxygen tension affects RCC cells. Hypoxia facilitates induction of sorafenib resistance in pRCC and induces map2k1 overexpression, while normoxic axitinib-resistant cells up-regulated eif4b. Further studies may determine if map2k1 or eif4b proteins play a role in pRCC resistance to TKIs. It is also of interest to establish if other than vegfr-1, braf, c-kit receptors can serve as potential molecular targets for more effective anti-RCC strategies.

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Section: Discussionmentioning

confidence: 99%

Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells

et al. 2017

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“…Thus, angiogenesis inhibition may be a viable treatment approach for the highly vascular tumor types, such as ovarian cancer, lung cancer and breast cancer [5][6][7]. However, targeting single factor may produce drug resistance and compensatory angiogenesis because the roles of other factors may be strengthened [8]. Several inhibitors of growth factor, receptor and kinases such as Bevacizumab, Ramucirumab, Aflibercept, Sunitinib, Sorafenib, and Pazopanib have been brought to clinical treatment for malignant tumors but most of these approaches are based on the physiological effects of single pathway, which may be insufficient to induce enduring anti-tumor efficacy [9].…”

Section: Introductionmentioning

confidence: 99%

Large‐scale production, purification, and function of a tumor multi‐epitope vaccine: Peptibody with bFGF/VEGFA

Zhang

Jiang

Chen

et al. 2020

Engineering in Life Sciences

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In tumor tissue, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) promote tumorigenesis by activating angiogenesis, but targeting single factor may produce drug resistance and compensatory angiogenesis. The Peptibody with bFGF/VEGFA was designed to simultaneously blockade these two factors. We were aiming to produce this Fc fusion protein in a large scale. The biological characterizations of Peptibody strains were identified as Escherichia coli and the fermentation mode was optimized in the shake flasks and 10‐L bioreactor. The fermentation was scaled up to 100 L, with wet cell weight (WCW) 126 g/L, production 1.41 g/L, and productivity 0.35 g/(L·h) of IPTG induction. The target protein was isolated by cation‐exchange, hydrophobic and Protein A chromatography, with total recovery of 60.28% and HPLC purity of 86.71%. The host cells protein, DNA, and endotoxin residues were within the threshold. In mouse model, immunization of Peptibody vaccine could significantly suppressed the tumor growth and angiogenesis, with inhibition rate of 57.73 and 39.34%. The Peptibody vaccine could elicit high‐titer anti‐bFGF and anti‐VEGFA antibodies, which inhibited the proliferation and migration of Lewis lung cancer cell cells by decreasing the Akt/MAPK signal pathways. Therefore, the Peptibody with bFGF/VEGFA might be used as a therapeutic tumor vaccine. The large‐scale process we developed could support its industrial production and pre‐clinical study in the future.

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“…We searched the Gene Expression Omnibus(GEO) database, identified the following 2 sets of microarray data regarding renal cell carcinoma resistance to RTK inhibitors, and included these data in our study: GSE76068 [ 22 ] and GSE64052 [ 23 ]. In GSE76068, researchers implanted 8 RCC patient-derived xenografts in mice and then treated these mice with sunitinib for approximately 4 weeks, at which time drug resistance developed.…”

Section: Resultsmentioning

confidence: 99%

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

Gao

Qiao

et al. 2016

Oncotarget

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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.

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MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model

Cited by 38 publications

References 39 publications

Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells

Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells

Large‐scale production, purification, and function of a tumor multi‐epitope vaccine: Peptibody with bFGF/VEGFA

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

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