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bioRxiv · 10.1101/2025.05.29.621197

Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma

Wang, X.·Duong, L.·Qin, Y.·Parrotta, R.·Purohit, P. K.·Fang, Y.·Liu, G.·He, J.·Wen, J.·Liu, Y.·Zhang, Y.·Zhao, J.·Schafer, Z. T.·Lu, X.·Szegezdi, E.
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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- (HIF, especially HIF2) plays an essential role in ccRCC initiation and progression. The approved HIF2 inhibitor belzutifan faces the challenge of resistance, presenting an opportunity of co-targeting HIF2 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 HIF2 and TRAIL. TRAIL was identified as a direct transcriptional target of HIF2 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 HIF2 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/621197v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1d603b9org.highwire.dtl.DTLVardef@18e6dc7org.highwire.dtl.DTLVardef@1c953cdorg.highwire.dtl.DTLVardef@9cd144_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wang, X., Duong, L., Qin, Y., Parrotta, R., Purohit, P. K., Fang, Y., Liu, G., He, J., Wen, J., Liu, Y., Zhang, Y., Zhao, J., Schafer, Z. T., Lu, X., Szegezdi, E.. 2025-05-30. Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma. https://doi.org/10.1101/2025.05.29.621197

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