Activation of RyR2 by class I kinase inhibitors

Area of Science:

• Cardiovascular Pharmacology
• Cancer Therapeutics
• Molecular Cardiology

Background:

• Kinase inhibitors are vital cancer treatments, with Class I inhibitors targeting ATP-binding pockets being common.
• Many kinase inhibitors exhibit cardiotoxicity, leading to arrhythmias.
• Store overload-induced Ca2+ release (SOICR) via cardiac ryanodine receptors (RyR2) is a key mechanism in arrhythmia development.

Purpose of the Study:

• To investigate if Class I kinase inhibitors modify RyR2 activity and trigger SOICR, contributing to their cardiotoxicity.
• To determine the effects of Class II kinase inhibitors on RyR2 and SOICR.
• To assess the reversibility of drug-induced SOICR using anti-SOICR agents.

Main Methods:

• Utilized single-cell Ca2+ imaging in HEK293 cells and ventricular myocytes to study kinase inhibitor effects on SOICR.
• Employed single channel recordings to confirm specific effects on RyR2.
• Tested the efficacy of anti-SOICR agents in reversing drug-induced SOICR in ventricular myocytes.

Main Results:

• Class I kinase inhibitors significantly increased SOICR propensity, specifically by affecting RyR2.
• Class II kinase inhibitors reduced RyR2 activity at the single channel level but did not substantially impact SOICR.
• The SOICR promotion by Class I inhibitors was successfully reversed by the anti-SOICR agent VK-II-86.

Conclusions:

• The cardiotoxicity of Class I kinase inhibitors is partly attributable to their interaction with RyR2 and subsequent increase in SOICR.
• Compounds possessing anti-SOICR activity hold promise as potentially safer therapeutic options for patients.
• Targeting RyR2 and SOICR offers a potential strategy to mitigate kinase inhibitor-induced cardiotoxicity.