Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel–Lindau (VHL) and the consequent activation of hypoxia-inducible factor-α (HIFα, especially HIF2α) plays an essential role in ccRCC initiation and progression. The VHL–HIF2α axis as the main driver for ccRCC may present specific opportunities to control the disease by cotargeting HIF2α with belzutifan and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC. Upregulated in ccRCC in a VHL–HIF2α-dependent manner, TRAIL is selectively essential in ccRCC cells, promoting cell proliferation by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cell and tumor models to recombinant TRAIL, presenting a promising avenue for combination therapy in ccRCC.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Xuechun Wang
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Yujing Qin
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Loan D. Duong
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Minzhi Liang
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Adrian Chao
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Rossella Parrotta
School of Chemical and Biological Sciences, University of Galway
Yaoyin Li
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Paresh Kumar Purohit
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Yihao Fang
Department of Applied and Computational Mathematics and Statistics, University of Notre Dame
Guoqiang Liu
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Jianping He
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Jiling Wen
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Yan Liu
Yuting Zhang
Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen, Guangdong, China.
Junling Zhao
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Nipuni Barupala
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Zachary T. Schafer
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Xuemin Lu
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame
Eva Szegezdi
School of Chemical and Biological Sciences, University of Galway
Xin Lu