Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL)1,2. Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal3, VHL inactivation is regarded as the governing event4. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells5. HIF-2 has been implicated in angiogenesis and multiple other processes6,7,8,9, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib10. HIF-2 has been regarded as undruggable11. Here we use a tumourgraft/patient-derived xenograft platform12,13 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)14 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 target15 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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Sequence Read Archive
We thank the patients who generously provided tissues and participated in our studies. PT2399 was provided by Peloton Therapeutics, Inc. Funding was provided by Peloton Therapeutics, Inc. (OTD-105466), CPRIT (RP160440) and philanthropy, including the Tom Green memorial. W.C. is supported by grants from the National Natural Science Foundation of China (No. 811011934) and the Science and Technology Program of Guangzhou, China (No. 2012J5100031). M.S.K. and H.Z. are supported by a grant from CPRIT (RP150596). I.P. is supported by grants from the NIH (R01CA154475, P50CA196516). X.S. is supported by a grant from CPRIT (RP110771). J.B. is a Virginia Murchison Linthicum endowed scholar and is supported by grants from the NIH (R01CA175754, P50CA196516, P30CA142543) and CPRIT (RP130603). R.K.B. is the Michael L. Rosenberg Scholar in Medical Research and was supported by CPRIT (RP130513). Histology equipment was purchased with funding from the National Center for Advancing Translational Sciences (Center for Translational Medicine UL1TR001105).
This file contains Supplementary Figure 1(gel source data) and Supplementary Figure 2 (Tumor dimensions).