Influence of VEGFR single nucleotide polymorphisms on the efficacy of sunitinib therapy against renal cell carcinoma

Rui Liu; Xiaojie Wang; Wei Li; Tao Shou; Likun Zhou; Yunfen Li; Ming Bai; Qiang Pei

doi:10.3892/ol.2016.5396

Influence of VEGFR single nucleotide polymorphisms on the efficacy of sunitinib therapy against renal cell carcinoma

Oncol Lett. 2017 Jan;13(1):201-205. doi: 10.3892/ol.2016.5396. Epub 2016 Nov 18.

Authors

Rui Liu¹, Xiaojie Wang¹, Wei Li², Tao Shou¹, Likun Zhou³, Yunfen Li⁴, Ming Bai³, Qiang Pei⁵

Affiliations

¹ Department of Oncology, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China.
² Department of Urological Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China.
³ Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
⁴ Department of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, Yunnan 650118, P.R. China.
⁵ Department of Hematology, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China.

Abstract

Single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor receptor (VEGFR) may have effects on the MAPK/ERK/STAT3 signaling pathway, and the resulting phenotypes may influence the response to sunitinib-targeted therapy for renal cell carcinoma. In order to test this hypothesis patients with advanced renal cell carcinoma treated with sunitinib, were enrolled in our study. Peripheral blood samples were used to run a polymerase chain reaction-restriction fragment length polymorphism protocol to type candidate nucleotide polymorphism loci (VEGFR1, VEGFR2 and VEGFR3). The samples were also used in western blots to determine p-MAPK/ERK/STAT3 protein expression levels. The clinical responses to treatment were recorded and then a logistic regression method was applied to analyze the correlation between polymorphism of loci and effectiveness of sunitinib therapy. According to a follow-up visit (on average after 15 months of treatment) there were 16 complete responses (CR), 29 partial responses (PR) and 23 stable disease (SD) and progression of disease (PD) cases. Tests were carried out for 5 SNPs: VEGFR1 (rs664393), VEGFR2 (rsl870377 and rs7667298) and VEGFR3 (rs448012 and rs72816988). Mutation rates of rsl870377 and rs448012 loci in the CR+PR group were lower than those in the SD+PD group. No such differences were found for the other 3 loci. Relative expression levels of p-MAPk, p-ERK and p-STAT3 in the CR+PR group were significantly lower than those in the SD+PD group (P<0.05). The median progression-free survival and overall survival (OS) in the CR+PR group were higher than those in the SD+PD group (P<0.001). The median OS of the TT rsl870377 genotype was higher than that of the AA genotype, and the median OS of the GG rs448012 genotype was higher than that of the CC genotype (P<0.001). It was concluded through a logistic regression model that rsl870377 (AA) and rs448012 (GG) are independent risk factors closely associated with the effectiveness of sunitinib-targeted therapy on renal cell carcinoma. VEGFR SNPs are able to mediate the MAPK/ERK/STAT3 signaling pathway and therefore influence the effectiveness of sunitinib-targeted therapy, which makes them possible new therapeutic targets.

Keywords: MAPK/ERK/STAT3 signaling pathway; renal cell carcinoma; single nucleotide polymorphism; sunitinib; targeted therapy; vascular endothelial growth factor receptor.