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

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