Targeting renal cell carcinoma with a HIF-2 antagonist
Autor: | Paul Yell, Farrah Homayoun, Xiankai Sun, Ivan Pedrosa, Naseem J. Zojwalla, Tae Hyun Hwang, Andrea Pavia-Jimenez, Wallace Eli M, Tai Wong, Wenfang Chen, Allison Joyce, Nirav V. Patel, Renée M. McKay, Xian Jin Xie, James Brugarolas, Kevin D. Courtney, James P. Rizzi, Payal Kapur, Kevin H. Gardner, Eboni Holloman, Haley Hill, Min Kim, Richard K. Bruick, John A. Josey, Alana Christie, Jenny Chang, He Zhang, Eugene P. Frenkel, Yuanqing Ma, Heather Geiger, Guiyang Hao, Yang Xie, Qurratulain Yousuf, Catherine Reeves |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Indoles Mice SCID Biology Article Mice 03 medical and health sciences Mice Inbred NOD Renal cell carcinoma In vivo Cell Line Tumor Basic Helix-Loop-Helix Transcription Factors Sunitinib medicine Carcinoma Animals Humans Pyrroles Molecular Targeted Therapy Sulfones Carcinoma Renal Cell Erythropoietin Transcription factor Binding Sites Multidisciplinary Aryl Hydrocarbon Receptor Nuclear Translocator Reproducibility of Results Cancer medicine.disease Xenograft Model Antitumor Assays Kidney Neoplasms Gene Expression Regulation Neoplastic Clear cell renal cell carcinoma Cell Transformation Neoplastic 030104 developmental biology Drug Resistance Neoplasm Cell culture Indans Mutation Immunology Cancer research Female medicine.drug |
Zdroj: | Nature. 539:112-117 |
ISSN: | 1476-4687 0028-0836 |
DOI: | 10.1038/nature19796 |
Popis: | 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. |
Databáze: | OpenAIRE |
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