Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control

Area of Science:

• Biochemistry
• Physiology
• Oncology

Background:

• Hypoxia-inducible factor (HIF) is upregulated in many cancers, leading to interest in HIF inhibitors as therapeutics.
• Small molecules targeting HIF-2α's PAS-B domain are in clinical trials for cancers driven by HIF-2.
• A key question is whether these inhibitors affect physiological responses to hypoxia at therapeutic doses.

Purpose of the Study:

• To investigate the physiological effects of HIF-2α inhibition on ventilatory responses to hypoxia.
• To determine if PT2385 affects ventilatory acclimatization and carotid body cell proliferation under hypoxic conditions.
• To confirm the on-target effects of PT2385 using a HIF-2α mutant mouse model.

Main Methods:

• Pharmacological inhibition of HIF-2α using PT2385 in mice.
• Assessment of ventilatory responses to sustained hypoxia.
• Utilizing a HIF-2α PAS-B S305M mutant mouse model to distinguish on-target from off-target effects.
• Evaluation of carotid body cell proliferative responses.

Main Results:

• PT2385 treatment rapidly impaired ventilatory responses to hypoxia at doses relevant to tumor growth inhibition.
• The drug abrogated both ventilatory acclimatization and carotid body cell proliferation during sustained hypoxia.
• Mice with a PT2385-resistant HIF-2α mutation showed no response to the drug, confirming on-target effects.
• HIF-2α mutant mice exhibited a hypomorphic ventilatory phenotype, suggesting a role beyond HIF-1β dimerization.

Conclusions:

• Pharmacological HIF-2α inhibition with PT2385 impacts critical physiological responses to hypoxia.
• These findings highlight the need for caution when using HIF-2α inhibitors in patients dependent on hypoxic ventilatory drive.
• The study reveals a potential physiological function for the HIF-2α PAS-B domain independent of HIF-1β heterodimerization.