Cardiovascular toxicity of PI3Kα inhibitors

Abstract

The phosphoinositide 3-kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 3′-hydroxyl group of inositol membrane lipids, resulting in the production of phosphatidylinositol 3,4,5-trisphosphate from phosphatidylinositol 4,5-bisphosphate. This results in downstream effects, including cell growth, proliferation, and migration. The heart expresses three PI3K class I enzyme isoforms (α, β, and γ), and these enzymes play a role in cardiac cellular survival, myocardial hypertrophy, myocardial contractility, excitation, and mechanotransduction. The PI3K pathway is associated with various disease processes but is particularly important to human cancers since many gain-of-function mutations in this pathway occur in various cancers. Despite the development, testing, and regulatory approval of PI3K inhibitors in recent years, there are still significant challenges when creating and utilizing these drugs, including concerns of adverse effects on the heart. There is a growing body of evidence from preclinical studies revealing that PI3Ks play a crucial cardioprotective role, and thus inhibition of this pathway could lead to cardiac dysfunction, electrical remodeling, vascular damage, and ultimately, cardiovascular disease. This review will focus on PI3Kα, including the mechanisms underlying the adverse cardiovascular effects resulting from PI3Kα inhibition and the potential clinical implications of treating patients with these drugs, such as increased arrhythmia burden, biventricular cardiac dysfunction, and impaired recovery from cardiotoxicity. Recommendations for future directions for preclinical and clinical work are made, highlighting the possible role of PI3Kα inhibition in the progression of cancer-related cachexia and female sex and pre-existing comorbidities as independent risk factors for cardiac abnormalities after cancer treatment.

Cardiac Safety of Kinase Inhibitors – Improving Understanding and Prediction of Liabilities in Drug Discovery Using Human Stem Cell-Derived Models

“…The cardiotoxic effects observed in hSC-CMs incubated with HS-173 clearly illustrates a decisive role the PI3K-α signaling inhibition plays in the process of cell death in the heart. In line with our finding, previous studies demonstrated that the use of PI3K-α inhibitors may directly or indirectly compromise cardiac function ( 55 ). The PI3K-α pathway inhibition promoted heart atrophy, biventricular remodeling, and increased susceptibility to doxorubicin toxicity in mice ( 56 ).…”

Osimertinib induced cardiac failure and QT-prolongation in a patient with advanced pulmonary adenocarcinoma

“…Therefore, key factor of QT prolongation in this case is not determined easily, because the age per se is a risk factor of QT prolongation. 14 In the AURA3 study QT interval prolongation occurred in 4% of patients in the Osimertinib group. Overall, QTcF interval increased by a median of 12.45 ms among patients randomized to Osimertinib.…”

A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for Osimertinib

“…Based on all the facts we speculated that HER2 was the main cause of osimertinib cardiotoxicity. The risk factors of cardiotoxicity caused by antitumor drugs include age, potential heart disease, renal insu ciency, and the combination of other cardiotoxic drugs, while the risk of cardiotoxicity caused by EGFR-TKI is more closely related to the patient's cardiovascular history (27). Thus, the early awareness of cardiotoxicities, monitoring for QT prolongation, managing symptoms of heart failure, and close follow-up, may enhance the bene ts of therapy while taking osimertinib.…”