Journal Article

Targeting renal cell carcinoma with a HIF-2 antagonist

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

2016

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Animals / Aryl Hydrocarbon Receptor Nuclear Translocator - genetics / Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism / Basic Helix-Loop-Helix Transcription Factors - antagonists & inhibitors / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Binding Sites / Carcinoma, Renal cell / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - metabolism / Carcinoma, Renal Cell - pathology / Cell Line, Tumor / Cell Transformation, Neoplastic / Drug Resistance, Neoplasm - drug effects / Erythropoietin - antagonists & inhibitors / Erythropoietin - blood / Female / Gene Expression Regulation, Neoplastic / Humans / Indans - administration & dosage / Indans - pharmacology / Indans - therapeutic use / Indoles - pharmacology / Indoles - therapeutic use / Kidney Neoplasms - drug therapy / Kidney Neoplasms - genetics / Kidney Neoplasms - metabolism / Kidney Neoplasms - pathology / Male / Methods / Mice / Mice, Inbred NOD / Mice, SCID / Molecular Targeted Therapy / Mutation / Physiological aspects / Pyrroles - pharmacology / Pyrroles - therapeutic use / Renal cell carcinoma / Reproducibility of Results / Sulfones - administration & dosage / Sulfones - pharmacology / Sulfones - therapeutic use / Sunitinib / Transcription factors / Xenograft Model Antitumor Assays