Video Experimental Relacionado

Updated: Dec 4, 2025

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Fibrillación auricular mediada por Ibrutinib atribuible a la inhibición de la C-Terminal Src Kinasa

Ling Xiao¹, Joe-Elie Salem^2,3,4, Sebastian Clauss^1,5,6

¹Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA.

|October 23, 2020

Resumen

Ibrutinib causa fibrilación auricular (FA) mediante la inhibición de la C-terminal Src quinasa (CSK), un efecto fuera de objetivo. Este descubrimiento explica un efecto secundario clave de este medicamento contra el cáncer de células B.

Área de la Ciencia:

Cardiología
En el campo de la oncología
Farmacología

Sus antecedentes:

Ibrutinib, un inhibidor de la tirosina quinasa de Bruton, es eficaz contra los cánceres de células B, pero aumenta el riesgo de fibrilación auricular (FA).
El mecanismo subyacente a la FA inducida por ibrutinib no se comprende bien.

Objetivo del estudio:

Investigar los efectos electrofisiológicos de ibrutinib en ratones.
Identificar las dianas moleculares responsables de la FA inducida por ibrutinib.
Confirmar la asociación entre los objetivos identificados y la FA en los datos de farmacovigilancia en humanos.

Principales métodos:

Estudios de electrofisiología en ratones tratados con ibrutinib.
Análisis quimioproteómico para identificar las dianas cardíacas de ibrutinib.
Modelos genéticos de ratón (nocaut de tirosina de Bruton, nocaut de Csk específico para el corazón) y experimentos farmacológicos.
Análisis de la base de datos de farmacovigilancia de VigiBase.

Principales resultados:

El tratamiento con Ibrutinib en ratones indujo FA, agrandamiento de la aurícula izquierda, fibrosis e inflamación.
La inducción de la FA por ibrutinib fue independiente de la tirosina quinasa de Bruton, pero relacionada con la inhibición fuera del objetivo.
La cinasa Src terminal C (CSK) fue identificada como la principal cinasa fuera del objetivo responsable de la FA inducida por ibrutinib.
Efectos del tratamiento con ibrutinib específicos para el corazón en ratones con knockout Csk fenocopiados.
El análisis de VigiBase mostró una asociación significativa entre los inhibidores de la CSK y el aumento de los informes de AF (OR=8,0).

Conclusiones:

La inhibición de la CSK es el mecanismo que impulsa la FA inducida por ibrutinib.
Este hallazgo identifica una vía molecular específica para un efecto secundario clínico significativo.
La comprensión de este mecanismo puede informar estrategias para mitigar el riesgo de FA en pacientes tratados con ibrutinib o inhibidores de la quinasa similares.

Palabras clave:

Proteína BTK, humana La proteína tirosina quinasa de la CSK Fibrilación auricular electrofisiología ybrutinib Inhibidores de la proteína quinasa

Más Videos Relacionados

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

Videos de Conceptos Relacionados

Intracellular Signaling Affects Focal Adhesions

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...

Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers

Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers

Class III antiarrhythmic drugs are a group of medications that can prolong action potentials in the heart. They achieve this by blocking potassium channels or enhancing inward currents from sodium channels. However, these drugs have a unique property of "reverse use-dependence," which is most pronounced at slower heart rates and can lead to torsades de pointes—a specific type of arrhythmia. However, it is essential to note that excessive QT interval prolongation—a measure of...

Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers

Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers

Adrenergic stimulation generally impacts cardiac rate and rhythm. Specifically, stimulation of the β-adrenoceptors triggers an increase in intracellular calcium ion influx and pacemaker currents, which may cause arrhythmias. Catecholamines like adrenaline also demonstrate β2-adrenoceptor-mediated hypokalemia, impacting cardiac action potential and disrupting the normal cardiac rhythm. Class II antiarrhythmic drugs are β-adrenoceptor antagonists or β-blockers, which...

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...

Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers

Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers

Class IV antiarrhythmic drugs, such as verapamil and diltiazem, block calcium channels. They primarily affect the heart, slowing the conduction in calcium-dependent tissues like the SA and AV nodes. These drugs manage reentrant supraventricular tachycardia (SVT) and reduce ventricular rate in atrial flutter/fibrillation.
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...