Investigating Cardiotoxicity of Osimertinib: Mechanisms and Therapeutic Interventions

About This Grant

Project summary Kinase inhibitors (KIs) represent critical advances in cancer treatment, yet their cardiac toxicity profiles are poorly understood. Recent clinical reports highlight significant cardiotoxicity associated with osimertinib, the sole approved therapy for EGFR T790M-positive non-small cell lung cancer (NSCLC). Approximately 3-5% of patients experience clinically significant cardiac adverse effects, including reduced left ventricular ejection fraction, heart failure, and arrhythmias, leading to treatment interruptions or discontinuation. Despite this significant clinical challenge and potential negative impact on patient survival, the underlying molecular mechanisms remain unexplored. Our preliminary studies in mouse models demonstrate early cardiac dysfunction linked to mitochondrial reactive oxygen species (mtROS) generation and increased NOX4 expression following osimertinib treatment. Clinical evidence also suggests that cardiac dysfunction, although often reversible, can seriously compromise the continuity of cancer treatment, emphasizing the urgent need for effective preventive strategies. We propose mitochondrial oxidative stress as a key driver of cardiotoxicity of osimertinib, warranting further mechanistic investigation. This research aims to elucidate the molecular mechanism of osimertinib- induced cardiotoxicity and to evaluate therapeutic strategies targeting mitochondrial dysfunction and oxidative stress through three specific aims. Aim 1 will determine the mitochondrial mechanisms underlying osimertinib-induced cardiotoxicity. Utilizing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we will measure mitochondrial function (oxygen consumption rate, mtROS levels, mitochondrial dynamics) to validate our hypothesis that mitochondrial bioenergetics disruption drives cardiac injury. Aim 2 will assess the role of NOX4 in mediating cardiac dysfunction. We will use transgenic and knockout mouse models, specifically altering cardiac NOX4 expression, to define its contribution to osimertinib-induced oxidative stress and mitochondrial impairment. In aim 3 we will evaluate cardioprotective strategies with mitochondrial-targeted antioxidants and NOX4 inhibitors. We will test MitoQ (mtROS scavenger) and setanaxib (NOX4 inhibitor), individually and in combination, to assess their efficacy in preventing osimertinib- induced cardiac damage both in vitro and in vivo. This study addresses a critical clinical issue by uncovering novel molecular insights into KI-induced cardiotoxicity, specifically identifying mitochondrial oxidative stress and NOX4 as therapeutic targets. Our findings aim to mitigate cardiac side effects associated with osimertinib, enhancing the clinical safety and efficacy of targeted cancer therapies, and thereby enabling uninterrupted cancer treatment and improving patient outcomes.