Cardiotoxicity of Kinase inhibition

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Remote access: https://oulu.zoom.us/j/64149117156

Topic of the dissertation

Cardiotoxicity of Kinase inhibition

Doctoral candidate

Master of Science Manar Elmadani

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, Research Unit of Biomedicine

Subject of study

Pharmacology and Toxicology

Opponent

Professor Kirsti Ytrehus, University of Tromsø

Custos

Professor Risto Kerkelä, University of Oulu

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Cardiotoxicity of Kinase inhibition

Small molecule kinase inhibitors (KIs) are a new class of anti-cancer agents that have dramatically improved the prognosis of many cancers, transforming them from a life-threatening disease to chronic illness.

Treatment of cancer patients with some KIs is associated with cardiotoxicity, including hypertension, myocardial ischemia, left ventricular dysfunction and heart failure. Understanding the mechanisms underlying cardiotoxicity will enable the design of KIs with less or no cardiovascular side effects and is beneficial for the identification and monitoring of patients with an increased risk for cardiotoxic side effects.

The studies included screening of 140 KIs for their cardiomyocyte toxicity in vitro and a focus on the cardiotoxic effects of the KI sorafenib in mice in vivo.

The screening identified the phosphoinositide 3‐kinase catalytic subunit alpha (PI3Kα), insulin like growth factor 1 and mammalian target of rapamycin (mTOR) as crucial kinases for cardiomyocyte viability. Interestingly, dual inhibition of PI3K and mTOR reduced cell viability and induced cardiomyocyte necrotic cell death.

Studies on sorafenib revealed that cardiotoxicity is induced via rapid induction of endothelial cell damage in mouse hearts and that sorafenib-induced cardiotoxicity is reversible. Moreover, modulation of angiopoietin signaling affected sorafenib induced cardiotoxicity. In conclusion, the decrease in cardiomyocyte viability caused by dual inhibition of PI3K and mTOR kinases may have relevance for future drug design targeting the PI3K/mTOR pathway. Angiopoietins play a key role in endothelial cell response to sorafenib treatment and sorafenib-induced cardiotoxicity.
Last updated: 2.12.2020