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Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control
- Source :
- The Journal of Clinical Investigation
- Publication Year :
- 2019
-
Abstract
- Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer and there is great interest in applying inhibitors of HIF as anti-cancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors impact on physiological responses to hypoxia at relevant doses. Here we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumour growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatisation and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerisation with HIF-1β, did not respond to PT2385 indicating that these effects are on target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerisation with HIF-1β. Although PT2385 was well-tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.
- Subjects :
- 0301 basic medicine
Gene isoform
Cell
Mutant
Mutation, Missense
Therapeutics
Pharmacology
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
medicine
Basic Helix-Loop-Helix Transcription Factors
Animals
Sulfones
Cancer
business.industry
hypoxia
Respiration
Aryl Hydrocarbon Receptor Nuclear Translocator
General Medicine
Hypoxia (medical)
Phenotype
Mice, Mutant Strains
3. Good health
030104 developmental biology
medicine.anatomical_structure
Amino Acid Substitution
030220 oncology & carcinogenesis
Indans
Carotid body
medicine.symptom
Antagonism
business
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 130
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....99c7feb495a88921d908dc50bd6a624e