Wang Xuechun, Duong Loan, Qin Yujing, Parrotta Rossella, Purohit Paresh Kumar, Fang Yihao, Liu Guoqiang, He Jianping, Wen Jiling, Liu Yan, Zhang Yuting, Zhao Junling, Schafer Zachary T, Szegezdi Eva, Lu Xin
Department of Biological Sciences, Boler-Parseghian Center for Rare Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN, 46556, USA.
bioRxiv. 2025 May 30:2025.05.29.621197. doi: 10.1101/2025.05.29.621197.
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of ( and the consequent activation of hypoxia-inducible factor-α (HIFα, especially HIF2α) plays an essential role in ccRCC initiation and progression. The approved HIF2α inhibitor belzutifan faces the challenge of resistance, presenting an opportunity of co-targeting HIF2α and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC, uncovering a novel reciprocal regulation between HIF2α and TRAIL. TRAIL was identified as a direct transcriptional target of HIF2α and paradoxically found to be crucial for cell proliferation, primarily by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2α with belzutifan sensitizes ccRCC cells to recombinant TRAIL, presenting a promising avenue for combination therapy to overcome both TRAIL resistance and belzutifan resistance in treating ccRCC.
透明细胞肾细胞癌（ccRCC）是最常见且侵袭性最强的肾癌亚型。VHL缺失（以及随之而来的缺氧诱导因子-α（HIFα，尤其是HIF2α）的激活）在ccRCC的起始和进展中起着至关重要的作用。已获批的HIF2α抑制剂belzutifan面临耐药性挑战，这为同时靶向HIF2α和另一个脆弱靶点提供了契机。本研究阐明了TRAIL（肿瘤坏死因子相关凋亡诱导配体）在VHL缺陷型ccRCC中的合成必要性，揭示了HIF2α与TRAIL之间一种新的相互调节关系。TRAIL被确定为HIF2α的直接转录靶点，并且矛盾的是，它主要通过激活p38丝裂原活化蛋白激酶途径和促进G1/S期转换，对细胞增殖至关重要。内源性TRAIL的缺失或用belzutifan抑制HIF2α可使ccRCC细胞对重组TRAIL敏感，这为联合治疗提供了一条有前景的途径，以克服在治疗ccRCC中TRAIL耐药性和belzutifan耐药性。
