Targeting renal cell carcinoma with a HIF-2 antagonist

Wenfang Chen, Haley Hill, Alana Christie, Min Soo Kim, Eboni Holloman, Andrea Pavia-Jimenez, Farrah Homayoun, Yuanqing Ma, Nirav Patel, Paul Yell, Guiyang Hao, Qurratulain Yousuf, Allison Joyce, Ivan Pedrosa, Heather Geiger, He Zhang, Jenny Chang, Kevin H. Gardner, Richard K. Bruick, Catherine Reeves & 14 others Tae Hyun Hwang, Kevin Courtney, Eugene Frenkel, Xiankai Sun, Naseem Zojwalla, Tai Wong, James P. Rizzi, Eli M. Wallace, John A. Josey, Yang Xie, Xian Jin Xie, Payal Kapur, Renée M. McKay, James Brugarolas

Research output: Contribution to journalArticle

167 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)112-117
Number of pages6
JournalNature
Volume539
Issue number7627
DOIs
StatePublished - 2016

Fingerprint

Renal Cell Carcinoma
Neoplasms
Carcinogenesis
Genetic Suppression
Mutation
Erythropoietin
Tumor Suppressor Genes
Transcriptome
Heterografts
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Genes
Transcription Factors
Biomarkers
Binding Sites
Clinical Trials
Gene Expression
Therapeutics
sunitinib

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Chen, W., Hill, H., Christie, A., Kim, M. S., Holloman, E., Pavia-Jimenez, A., ... Brugarolas, J. (2016). Targeting renal cell carcinoma with a HIF-2 antagonist. Nature, 539(7627), 112-117. https://doi.org/10.1038/nature19796

Targeting renal cell carcinoma with a HIF-2 antagonist. / 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.

In: Nature, Vol. 539, No. 7627, 2016, p. 112-117.

Research output: Contribution to journalArticle

Chen, W, Hill, H, Christie, A, Kim, MS, Holloman, E, Pavia-Jimenez, A, Homayoun, F, Ma, Y, Patel, N, Yell, P, Hao, G, Yousuf, Q, Joyce, A, Pedrosa, I, Geiger, H, Zhang, H, Chang, J, Gardner, KH, Bruick, RK, Reeves, C, Hwang, TH, Courtney, K, Frenkel, E, Sun, X, Zojwalla, N, Wong, T, Rizzi, JP, Wallace, EM, Josey, JA, Xie, Y, Xie, XJ, Kapur, P, McKay, RM & Brugarolas, J 2016, 'Targeting renal cell carcinoma with a HIF-2 antagonist', Nature, vol. 539, no. 7627, pp. 112-117. https://doi.org/10.1038/nature19796
Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112-117. https://doi.org/10.1038/nature19796
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. / Targeting renal cell carcinoma with a HIF-2 antagonist. In: Nature. 2016 ; Vol. 539, No. 7627. pp. 112-117.
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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.",
author = "Wenfang Chen and Haley Hill and Alana Christie and Kim, {Min Soo} and Eboni Holloman and Andrea Pavia-Jimenez and Farrah Homayoun and Yuanqing Ma and Nirav Patel and Paul Yell and Guiyang Hao and Qurratulain Yousuf and Allison Joyce and Ivan Pedrosa and Heather Geiger and He Zhang and Jenny Chang and Gardner, {Kevin H.} and Bruick, {Richard K.} and Catherine Reeves and Hwang, {Tae Hyun} and Kevin Courtney and Eugene Frenkel and Xiankai Sun and Naseem Zojwalla and Tai Wong and Rizzi, {James P.} and Wallace, {Eli M.} and Josey, {John A.} and Yang Xie and Xie, {Xian Jin} and Payal Kapur and McKay, {Ren{\'e}e M.} and James Brugarolas",
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T1 - Targeting renal cell carcinoma with a HIF-2 antagonist

AU - Chen, Wenfang

AU - Hill, Haley

AU - Christie, Alana

AU - Kim, Min Soo

AU - Holloman, Eboni

AU - Pavia-Jimenez, Andrea

AU - Homayoun, Farrah

AU - Ma, Yuanqing

AU - Patel, Nirav

AU - Yell, Paul

AU - Hao, Guiyang

AU - Yousuf, Qurratulain

AU - Joyce, Allison

AU - Pedrosa, Ivan

AU - Geiger, Heather

AU - Zhang, He

AU - Chang, Jenny

AU - Gardner, Kevin H.

AU - Bruick, Richard K.

AU - Reeves, Catherine

AU - Hwang, Tae Hyun

AU - Courtney, Kevin

AU - Frenkel, Eugene

AU - Sun, Xiankai

AU - Zojwalla, Naseem

AU - Wong, Tai

AU - Rizzi, James P.

AU - Wallace, Eli M.

AU - Josey, John A.

AU - Xie, Yang

AU - Xie, Xian Jin

AU - Kapur, Payal

AU - McKay, Renée M.

AU - Brugarolas, James

PY - 2016

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N2 - 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.

AB - 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.

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