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

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Clinical Epigenetics

, 7:99

First Online: 16 September 2015Received: 04 April 2015Accepted: 07 September 2015


BackgroundThe 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.

ResultsIn 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.

ConclusionsThe 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.

KeywordsVascular endothelial growth factor Vascular endothelial growth factor receptor Anti-vascular endothelial growth factor antibody Tyrosine kinase inhibitor Sunitinib Axitinib Renal cancer AbbreviationsDAC5-aza-2′-deoxycytidine

HUVEChuman umbilical vein endothelial cell

ODoptical density

RCCrenal cancer cell

RECISTResponse Evaluation Criteria in Solid Tumors

RPMIRoswell Park Memorial Institute medium

RQrelative quantity

RT-PCRreverse transcription polymerase chain reaction

VEGFvascular endothelial growth factor

VEGFRvascular endothelial growth factor receptor

Electronic supplementary materialThe online version of this article doi:10.1186-s13148-015-0134-9 contains supplementary material, which is available to authorized users.

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Author: Jee Yeon Kim - Junha Hwang - Seo Hyun Lee - Hyo Jin Lee - Jaroslav Jelinek - Hyeseon Jeong - Jae Sung Lim - Jin Man K


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