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Targeting renal cell carcinoma with a HIF-2 antagonist.

Authors: Chen, Wenfang  Hill, Haley  Christie, Alana  Kim, Min Soo  Holloman, Eboni  Pavia-Jimenez, Andrea  Homayoun, Farrah  Ma, Yuanqing  Patel, Nirav  Yell, Paul  Hao, Guiyang  Yousuf, Qurratulain  Joyce, Allison  Pedrosa, Ivan  Geiger, Heather  Zhang, He  Chang, Jenny  Gardner, Kevin H  Bruick, Richard K  Reeves, Catherine  Hwang, Tae Hyun  Courtney, Kevin  Frenkel, Eugene  Sun, Xiankai  Zojwalla, Naseem  Wong, Tai  Rizzi, James P  Wallace, Eli M  Josey, John A  Xie, Yang  Xie, Xian-Jin  Kapur, Payal  McKay, Renée M  Brugarolas, James 
Citation: Chen W, etal., Nature. 2016 Nov 3;539(7627):112-117. doi: 10.1038/nature19796. Epub 2016 Sep 5.
Pubmed: (View Article at PubMed) PMID:27595394
DOI: Full-text: DOI:10.1038/nature19796

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.


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RGD Object Information
RGD ID: 13503335
Created: 2018-01-11
Species: All species
Last Modified: 2018-01-11
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.