Journal article
Targeting renal cell carcinoma with a HIF-2 antagonist
Nature (London), Vol.539(7627), pp.112-117
11/03/2016
DOI: 10.1038/nature19796
PMCID: PMC5340502
PMID: 27595394
Abstract
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-1β) 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-1β, 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.
Details
- Title: Subtitle
- Targeting renal cell carcinoma with a HIF-2 antagonist
- Creators
- Wenfang Chen - Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of ChinaHaley Hill - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAAlana Christie - Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAMin Soo Kim - Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAEboni Holloman - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAAndrea Pavia-Jimenez - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAFarrah Homayoun - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAYuanqing Ma - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USANirav Patel - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAPaul Yell - Parkland Health and Hospital System, Dallas, Texas 75235, USAGuiyang Hao - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAQurratulain Yousuf - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAAllison Joyce - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAIvan Pedrosa - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAHeather Geiger - New York Genome Center, New York, New York 10013, USAHe Zhang - Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAJenny Chang - Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAKevin H Gardner - Biochemistry, Chemistry and Biology Ph.D. Programs, Graduate Center, City University of New York, New York, New York 10016, USARichard K Bruick - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USACatherine Reeves - New York Genome Center, New York, New York 10013, USATae Hyun Hwang - Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAKevin Courtney - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAEugene Frenkel - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAXiankai Sun - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USANaseem Zojwalla - Peloton Therapeutics Inc., Dallas, Texas 75235, USATai Wong - Peloton Therapeutics Inc., Dallas, Texas 75235, USAJames P Rizzi - Peloton Therapeutics Inc., Dallas, Texas 75235, USAEli M Wallace - Peloton Therapeutics Inc., Dallas, Texas 75235, USAJohn A Josey - Peloton Therapeutics Inc., Dallas, Texas 75235, USAYang Xie - Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAXian-Jin Xie - Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAPayal Kapur - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USARenée M McKay - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAJames Brugarolas - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.539(7627), pp.112-117
- Publisher
- England
- DOI
- 10.1038/nature19796
- PMID
- 27595394
- PMCID
- PMC5340502
- ISSN
- 1476-4687
- eISSN
- 1476-4687
- Grant note
- P30 CA142543 / NCI NIH HHS R01 CA154475 / NCI NIH HHS R01 CA175754 / NCI NIH HHS UL1 TR001105 / NCATS NIH HHS P50 CA196516 / NCI NIH HHS
- Language
- English
- Date published
- 11/03/2016
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917690102771
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