Dataset Information

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

ABSTRACT:

Background

Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model.

Methods

RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA.

Results

During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC.

Conclusions

Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy.

SUBMITTER: Diaz-Montero CM

PROVIDER: S-EPMC5061902 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Diaz-Montero C Marcela CM Mao Frances J FJ Barnard John J Parker Yvonne Y Zamanian-Daryoush Maryam M Pink John J JJ Finke James H JH Rini Brian I BI Lindner Daniel J DJ

British journal of cancer 20160825 8

<h4>Background</h4>Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model.<h4>Methods</h4>RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were as ...[more]

PMID: 27560553

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Project description:BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p<0.001) and prolonged survival (p=0.004) compared to the vehicle control.ConclusionsA metastatic PE-derived RMC PDX model was established and shown to maintain histologic features of the patient cancer. Molecular integrity of the PDX models was well maintained between renal tumor and PE PDX as well as between two successive renal tumor PDX generations. Using the PE PDX model, sunitinib demonstrated therapeutic efficacy for RMC. This model can serve as a foundation for future mechanistic and therapeutic studies for primary and metastatic RMC.

Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival. Study was comprised of three experimental groups (pre-treatment, response, escape). All tumors came from the same PDX model. There were four biological replicates in each group. Four mice were used, with each of the 3 groups per mouse. There were no control or reference samples.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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