Selective Estrogen Receptor Degraders Induce Bradycardia by Modulating Nuclear Estrogen Signaling

Area of Science:

• Molecular pharmacology
• Cardiovascular toxicology
• Endocrinology

Background:

• Selective estrogen receptor degraders (SERDs) are vital for treating estrogen receptor-positive (ER+) breast cancer.
• Clinical trials report bradycardia (slow heart rate) associated with some oral SERDs, like giredestrant and camizestrant.
• The molecular basis for SERD-induced bradycardia remains unclear.

Purpose of the Study:

• To investigate the molecular mechanism underlying bradycardia induced by oral SERDs.
• To determine the role of estrogen receptors (ERs) in SERD-associated cardiovascular adverse effects.

Main Methods:

• Utilized a zebrafish model to study SERD-induced bradycardia.
• Employed chemical biology and genetic approaches, including the use of ER agonists and knockout zebrafish.
• Assessed heart rate changes in response to various SERDs (giredestrant, camizestrant, fulvestrant, amcenestrant) and genetic mutations (gper, esr1, esr2a, esr2b).

Main Results:

• Giredestrant and camizestrant significantly induced bradycardia in wild-type zebrafish embryos.
• Fulvestrant and amcenestrant, which do not cause bradycardia in patients, did not affect zebrafish heart rate.
• Estrogen receptor 1 (Esr1) signaling was identified as the mediator; esr1 mutant zebrafish were protected from SERD-induced bradycardia.

Conclusions:

• SERD-associated bradycardia is mediated through estrogen receptor 1 (Esr1) signaling.
• The findings suggest that bradycardia linked to certain oral SERDs is an on-target adverse effect.
• This research provides crucial insights into the cardiovascular safety of SERD therapies.