Abstract
Simple SummaryClear cell renal cell carcinoma is a common malignancy that represents 80% of all kidney tumors. Most tumors harbor an inactivation of the VHL gene, leading to the accumulation of HIF-1α and HIF-2α. Promising clinical results of specific HIF-2α inhibitors will soon lead to new treatment options for advanced cancer patients, although primary and acquired resistance to these agents are common. We here show that Acriflavine, which inhibits both HIF-1α and HIF-2α, and Fingolimod (FTY720), which inhibits sphingosine-1-phosphate signaling, show therapeutic activities in several experimental ccRCC models that are resistant to HIF-2α-inhibitor treatment. Additionally, we show that specific HIF-2α-inhibition suppresses the tumor immune microenvironment, which will be important to consider for future combination studies with immune checkpoint inhibitors.Specific inhibitors of HIF-2α have recently been approved for the treatment of ccRCC in VHL disease patients and have shown encouraging results in clinical trials for metastatic sporadic ccRCC. However, not all patients respond to therapy and pre-clinical and clinical studies indicate that intrinsic as well as acquired resistance mechanisms to HIF-2α inhibitors are likely to represent upcoming clinical challenges. It would be desirable to have additional therapeutic options for the treatment of HIF-2α inhibitor resistant ccRCCs. Here we investigated the effects on tumor growth and on the tumor microenvironment of three different direct and indirect HIF-α inhibitors, namely the HIF-2α-specific inhibitor PT2399, the dual HIF-1α/HIF-2α inhibitor Acriflavine, and the S1P signaling pathway inhibitor FTY720, in the autochthonous Vhl/Trp53/Rb1 mutant ccRCC mouse model and validated these findings in human ccRCC cell culture models. We show that FTY720 and Acriflavine exhibit therapeutic activity in several different settings of HIF-2α inhibitor resistance. We also identify that HIF-2α inhibition strongly suppresses T cell activation in ccRCC. These findings suggest prioritization of sphingosine pathway inhibitors for clinical testing in ccRCC patients and also suggest that HIF-2α inhibitors may inhibit anti-tumor immunity and might therefore be contraindicated for combination therapies with immune checkpoint inhibitors.
Highlights
The defining genetic feature of the vast majority of clear cell renal cell carcinomas is biallelic inactivation of the von Hippel–Lindau (VHL) tumor suppressor gene [1].Loss of function of the pVHL protein prevents oxygen-dependent ubiquitin-mediated degradation of the HIF-1α and HIF-2α transcription factor subunits, leading to their constitutive stabilization and activation of transcription programs that contribute to numerous aspects of tumorigenesis
Model [2,14], the status of activation of transcription by Scm-like with four mbt domains 1 (SFMBT1) and of genes involved in the sphingosine 1-phosphate (S1P) signaling pathway was unknown
We have recently shown that tumor cell-specific deletion of Hif1a or Hif2a differently affect the tumor microenvironment in mouse clear cell renal cell carcinomas (ccRCC), with genetic deletion of Hif2a leading to a stronger anti-tumor response characterized by increased numbers of active CD8+ T
Summary
The defining genetic feature of the vast majority of clear cell renal cell carcinomas (ccRCC) is biallelic inactivation of the von Hippel–Lindau (VHL) tumor suppressor gene [1]. Several lines of correlative and functional genetic evidence have ascribed a predominant oncogenic role to HIF-2α [3,4,5], which led to the development of a series of chemically related specific HIF-2α inhibitors PT2399, PT2385, and PT2977 ( known as MK-6482 and as Belzutifan) which exhibits improved pharmacokinetics and is the molecule that has recently been clinically approved for the treatment of advanced tumors in VHL patients [6,7,8] These drugs block the interaction of HIF-2α with the ARNT transcriptional co-activator and thereby inhibit HIF-2-dependent transcriptional activity [9]. The efficacy was independent of a setting of specific HIF-2α-inhibitor resistance in vitro and in vivo, paving the way for future alternative ccRCC treatments
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