PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction

Abstract

Background Cancer therapies inhibiting PI3Kα (phosphoinositide 3‐kinase‐α)–dependent growth factor signaling, including trastuzumab inhibition of HER2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI3Kα is now in clinical trials, but the effects of PI3Kα pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results Pharmacological PI3Kα inhibition and heart‐specific genetic deletion of p110α, the catalytic subunit of PI3Kα, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI3Kα inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI3Kα signaling when combined with doxorubicin treatment. Increased p38 mitogen‐activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions PI3Kα pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen‐activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity.

Keywords

• anthracycline
• heart atrophy
• PI3K
• remodeling
• right ventricle