Clear cell Renal Cell Carcinoma (ccRCC) is characterized by VHL inactivation(1,2). Because no other gene is mutated as frequently, and VHL mutations are truncal(3), VHL inactivation is regarded as the governing event(4). VHL loss activates HIF-2, and constitutive HIF-2 restores tumorigenesis in VHL-reconstituted ccRCC cells(5). HIF-2 is implicated in angiogenesis and multiple other processes(6,7,8,9), but angiogenesis is the main target of drugs like sunitinib(10). HIF-2, a transcription factor, has been regarded as undruggable(11). A structure-based design approach identified a selective HIF-2 antagonist (PT2399) that we evaluate using a tumorgraft (TG)/PDX platform(12,13). PT2399 dissociated HIF-2 (an obligatory heterodimer [HIF-2α/HIF-1β])(14) in human ccRCC suppressing tumorigenesis in 56% (10/18) lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumors, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant. Resistance occurred despite HIF-2 dissociation in tumors and evidence of Hif-2 inhibition in the mouse as determined by suppression of circulating erythropoietin, a HIF-2 target(15) and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumors. Illustrating drug specificity, gene expression was largely unaffected by PT2399 in resistant tumors. Sensitive tumors exhibited a distinguishing gene expression signature, and generally higher HIF-2α levels. Prolonged PT2399 treatment led to resistance. We identified a binding site and second site suppressor mutation in HIF-2α and HIF-1β respectively. Both mutations preserved HIF-2 dimers despite PT2399. Finally, an extensively pretreated patient with a sensitive TG had disease control for >11 months with the close analogue PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCC are, unexpectedly, HIF-2 independent, and set the stage for biomarker-driven clinical trials.
Pharmacology, Toxicology and Pharmaceutical Science
17
4%
Other
50
11%
Unknown
131
29%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 256. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 April 2026.
All research outputs
#180,783
of 34,307,719 outputs
Outputs from Nature
#10,208
of 117,351 outputs
Outputs of similar age
#2,905
of 337,496 outputs
Outputs of similar age from Nature
#182
of 986 outputs
Altmetric has tracked 34,307,719 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 99th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 117,351 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 96.0. This one has done particularly well, scoring higher than 91% of its peers.
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We're also able to compare this research output to 986 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 81% of its contemporaries.
