Targeting renal cell carcinoma with a HIF-2 antagonist

The transcription factor HIF-2, an important driver of clear cell renal cell carcinoma, has been called 'undruggable'. However, in this issue of Nature, two groups report on the development and testing of a novel HIF-2 inhibitor, termed PT2399. William Kaelin and colleagues show that PT2399 causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma. James Brugarolas and colleagues tested the compound in mice with tumour grafts generated from human renal cell cancers. PT2399 decreased tumour growth in 10 out of 18 cell lines and was well tolerated. The authors identify potential markers of sensitivity and provide initial characterization of the effects and mechanisms of resistance acquisition in vivo. Both groups report variable sensitivity to PT2399 in some pVHL-defective cell lines, highlighting a need for predictive biomarkers to be developed for use of this approach in the clinic.