journal contribution
posted on 2023-03-31, 02:25 authored by Daniel J. Crona, Andrew D. Skol, Veli-Matti Leppänen, Dylan M. Glubb, Amy S. Etheridge, Eleanor Hilliard, Carol E. Peña, Yuri K. Peterson, Nancy Klauber-DeMore, Kari K. Alitalo, Federico Innocenti Expression of WT and T494A VEGFR-3 in HUVECs (A) and replication of phosphorylation experiments testing the effect of FLT4 rs307826 (A>G, T494A) on VEGFR-3 phosphorylation (B).
Funding
NIH
NCI
Cancer Research Foundation
NIGMS
American Foundation for Pharmaceutical Education
Jane and Aatos Erkko Foundation
Horizon 2020
Jenny and Antti Wihuri Foundation
Academy of Finland Centre of Excellence
Sigrid Juselius Foundation
History
ARTICLE ABSTRACT
Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC.
Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.
