Targeting renal cell carcinoma with a HIF-2 antagonist.
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.
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
Wenfang
W
Chen
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Haley
H
Hill
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Alana
A
Christie
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Min Soo
MS
Kim
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Eboni
E
Holloman
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Andrea
A
Pavia-Jimenez
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Farrah
F
Homayoun
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Yuanqing
Y
Ma
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nirav
N
Patel
Parkland Health and Hospital System, Dallas, Texas 75235, USA.
Paul
P
Yell
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Guiyang
G
Hao
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Qurratulain
Q
Yousuf
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Allison
A
Joyce
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Ivan
I
Pedrosa
New York Genome Center, New York, New York 10013, USA.
Heather
H
Geiger
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
He
H
Zhang
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Jenny
J
Chang
Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York 10031, USA.|Department of Chemistry and Biochemistry, City College of New York, New York, New York 10031, USA.|Biochemistry, Chemistry and Biology Ph.D. Programs, Graduate Center, City University of New York, New York, New York 10016, USA.
Kevin H
KH
Gardner
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Richard K
RK
Bruick
New York Genome Center, New York, New York 10013, USA.
Catherine
C
Reeves
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Tae Hyun
TH
Hwang
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Kevin
K
Courtney
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Eugene
E
Frenkel
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Xiankai
X
Sun
Peloton Therapeutics Inc., Dallas, Texas 75235, USA.
Naseem
N
Zojwalla
Peloton Therapeutics Inc., Dallas, Texas 75235, USA.
Tai
T
Wong
Peloton Therapeutics Inc., Dallas, Texas 75235, USA.
James P
JP
Rizzi
Peloton Therapeutics Inc., Dallas, Texas 75235, USA.
Eli M
EM
Wallace
Peloton Therapeutics Inc., Dallas, Texas 75235, USA.
John A
JA
Josey
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Yang
Y
Xie
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Xian-Jin
XJ
Xie
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Payal
P
Kapur
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Renée M
RM
McKay
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
James
J
Brugarolas
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000097:blood; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009154:Mutation; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D015203:Reproducibility of Results; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D007189:Indans; D007211:Indoles; D011758:Pyrroles; D013450:Sulfones; D000077210:Sunitinib; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse; C000614279:PT2385; C000614278:PT2399