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

Content Provider	Springer Nature : BioMed Central
Author	Arnaiz, Esther Miar, Ana Bridges, Esther Prasad, Naveen Hatch, Stephanie B. Ebner, Daniel Lawrie, Charles H. Harris, Adrian L.
Abstract	Background In 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. Methods We 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. Results PT2385 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.
Related Links	https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-021-08616-8.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
ISSN	14712407
DOI	10.1186/s12885-021-08616-8
Journal	BMC Cancer
Issue Number	1
Volume Number	21
Language	English
Publisher	BioMed Central
Publisher Date	2021-08-05
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Surgical Oncology Health Promotion and Disease Prevention Biomedicine Medicine Public Health HIF2α Renal cancer EMT Drug resistance Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology Genetics
Journal Impact Factor	3.4/2023
5-Year Journal Impact Factor	3.8/2023

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