Decreased efficacy of drugs targeting the vascular endothelial growth factor pathway by the epigenetic silencing of FLT1 in renal cancer cells

Clinical Epigenetics

Jei Kim⁶  Sukhoon Lee¹  Byung Hoon Kim³  Kyu Sang Song⁴  Jin Man Kim⁴  Jae Sung Lim⁷  Hyeseon Jeong²  Jaroslav Jelinek⁵  Hyo Jin Lee⁸  Seo Hyun Lee¹  Junha Hwang²  Jee Yeon Kim² 

[1] Department of Information and Statistics, College of Natural Science, Chungnam National University, Daejeon, South Korea;Neuroepigenetics Laboratory and Department of Neurology, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea;Department of Urology, Hospital and School of Medicine, Keimyung University, Daegu, South Korea;Department of Pathology, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea;Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA;Department of Neurology, Chungnam National University Hospital, 282 Moonhwa-ro, Daejeon, Joong-gu, South Korea;Department of Urology, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea;Department of Internal Medicine, Cancer Research Institute, Hospital and School of Medicine, Chungnam National University, Daejeon, South Korea

关键词: Renal cancer;    Axitinib;    Sunitinib;    Tyrosine kinase inhibitor;    Anti-vascular endothelial growth factor antibody;    Vascular endothelial growth factor receptor;    Vascular endothelial growth factor;   

Others  :  1225840
DOI  :  10.1186/s13148-015-0134-9

 received in 2015-04-04, accepted in 2015-09-07,  发布年份 2015

【 摘 要 】

Background

The vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling pathway is involved in cancer-related biological functions and is a therapeutic target in cancer. However, the influence of epigenetic regulation of VEGF-VEGFR signaling-related genes remains unclear. Here, we evaluated the effects of FLT1 and KDR promoter hypermethylation combined with drugs targeting VEGF-VEGFR signaling on cancer-related phenotypes in renal cancer cells (RCCs) and examined changes in FLT1 and KDR promoter hypermethylation in tissues from patients with renal cancer.

Results

In vitro experiments were performed to evaluate the effects of beavacizumab (an anti-VEGF antibody), an anti-FLT1 peptide, an anti-KDR antibody, and the VEGFR tyrosine kinase inhibitors (TKIs) sunitinib and axitinib in 13 RCC lines with different levels of FLT1 and/or KDR promoter methylation and in 2 FLT1 or KDR in vitro knockdown models. The synergistic effects of sunitinib and axitinib treatment were also evaluated in four RCC lines having different levels of FLT1 and/or KDR methylation. In our in vitro experiments, bevacizumab and an anti-KDR antibody did not affect the proliferation of RCCs having FLT1 and/or KDR hypermethylation. In contrast, in RCCs with FLT1 hypermethylation, proliferation inhibition was counteracted by treatment with an anti-FLT1 peptide and both VEGF-TKIs (sunitinib and axitinib). Demethylation with sunitinib or axitinib synergistically increased proliferation inhibition in the RCCs exhibiting FLT1 hypermethylation. Using in vitro FLT1 or KDR knockdown models, decreased proliferation inhibition following anti-FLT1 peptide, sunitinib, and axitinib treatment was observed only in FLT1-knockdown cells. In patients with renal cancer who received sunitinib, FLT1 promoter methylation was higher in renal cancer tissues from eight nonresponders (stable or progressive disease assessed by the Response Evaluation Criteria in Solid Tumors) than in cancer tissues from five responders (complete response or partial response).

Conclusions

The present data showed that hypermethylated FLT1 was important for the efficacy of anti-VEGF/VEGFR drugs targeting FLT1 or intracellular VEGFR signaling. FLT1 hypermethylation causing alterations of FLT1 function could serve as a useful biomarker for predicting changes in FLT1 status in RCCs.

【 授权许可】

   
2015 Kim et al.

【 图 表 】

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