Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs

BMC Cancer

Adrian L. Harris¹  Esther Arnaiz¹  Esther Bridges¹  Charles H. Lawrie²  Ana Miar³  Naveen Prasad³  Daniel Ebner⁴  Stephanie B. Hatch⁴ 

[1] Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DS, Oxford, UK;Department of Oncology, Molecular Oncology Group, Biodonostia Health Research Institute, Paseo Doctor Begiristain s/n, 20014, San-Sebastián, Spain;Department of Oncology, Old Road Campus Research Building, University of Oxford, OX3 7DQ, Oxford, UK;Nuffield Department of Medicine, NDM Research Building, University of Oxford, OX3 7DQ, Oxford, UK;

关键词: HIF2α;    Renal cancer;    EMT;    Drug resistance;   

DOI  :  10.1186/s12885-021-08616-8

来源: Springer

【 摘 要 】

BackgroundIn clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed.MethodsWe assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385.ResultsPT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

【 授权许可】

CC BY