Tyrosine kinase-targeting drugs-associated heart failure

Abstract

Background:The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF).Methods:A nested case–control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF.Results:There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46–2.49), cetuximab (OR 1.72, 1.10–2.69), panitumumab (OR 3.01, 1.02–8.85), and sunitinib (OR 3.39, 1.78–6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking.Conclusions:Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF.

Interference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects

“…New targeting strategies of ERK1/2 signaling are of major therapeutic interest, since permanent activation and inactivation of this cascade both appear detrimental. Novel ERK1/2 targeting strategies should increase the therapeutic efficacy by circumventing drug-resistance and reduce cardiac side-effects that currently limit their application 2,4,[56][57][58] . In this regard, interference with ERK dimerization holds promise, since AKT activation as one compensatory mechanism that contributes to drugresistance was prevented in HT29 cells, and most importantly no side-effects were detectable in the AAV9-EDI model nor for the overexpression of monomeric ERK2 ( Figs.…”

A Review of Matched-pairs Feature Selection Methods for Gene Expression Data Analysis

“…(v) Identifying drug targets. Gronich et al [ 86 ] evaluated the association between tyrosine kinase-targeting drugs and the risk of new-onset heart failure, using nested case-control analysis. (vi) Clinical supplementary diagnosis.…”

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models

“…In species cross activity analysis, heart endocardium, lung type II alveolar epithelial cell and surrounding vessels showed moderate positive staining of EGFR expression, but not in cardiac muscle fibers, indicating potential crossing binding APZ001 or anti-EGFR mAb drugs on heart endocardium cells and lung epithelial cells. Heart side-effects caused by Erbitux were reported [10][11][12] recently. They reported that patients might suffer from heart rate increase, sense of suppression in the chest, breathe hard and fatigue susceptibility, and even heart failure 10 .…”

“…Heart side-effects caused by Erbitux were reported [10][11][12] recently. They reported that patients might suffer from heart rate increase, sense of suppression in the chest, breathe hard and fatigue susceptibility, and even heart failure 10 . Overbeek et al 11 reported that Erbitux exposure was 1.72 fold OR (1.10-2.69) associated with increased heart failure risk.…”