Abstract P3110: Mechanism Of Cardiotoxicity Associated With Tyrosine Kinase Inhibitor Osimertinib

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for non-small cell lung cancer (NSCLC) treatment. Osimertinib potently and selectively inhibits EGFR-T790M resistance mutations in patients with NSCLC harboring these mutations. Emerging evidence from clinical trials has identified potential cardiotoxic effects of osimertinib including heart failure, atrial fibrillation (AF), and QT interval prolongation. The mechanisms underlying osimertinib-induced cardiotoxicity, however, are poorly understood. Methods: To investigate potential mechanisms of osimertinib-induced cardiotoxicity, we tested the drug in both in vitro cultured cardiomyocytes (CMs) and wild-type C57BL/6 mice in vivo , corresponding to doses used in preclinical development. Echocardiography was performed in mice to assess the effect on cardiac function. In vivo electrophysiology studies were also performed to assess effects on osimertinib-induced AF and QT prolongation susceptibility. Results: Osimertinib (500 nM, 72 hours) reduced CM viability in NRVMs (p=0.0001), and induced apoptosis as determined by TUNEL assay (p=0.004) and upregulated Bax/Bcl-2 ratio (mRNA: 1.45-fold, p=0.001). In wild-type C57BL/6 mice, osimertinib (5 mg/Kg/day, 4 weeks) decreased ejection fraction (37.15±3.99% vs control: 51.04±2.23%, p=0.0001) and fractional shortening (17.69±2.18% vs control: 25.56±1.51%, p=0.0001). This was associated with an increase in cardiac BNP expression (mRNA: 1.72-fold, p=0.005) and apoptotic Bax/Bcl-2 ratio (protein: 1.85-fold, p=0.02). Electrophysiology studies also demonstrated 2:1 atrioventricular block (p=0.03) in osimertinib treated mice and increased AF susceptibility. A combination of in vitro and in vivo mechanistic analyses demonstrated that osimertinib significantly inhibits pro-survival ERK signaling pathway. Conclusions: Our results demonstrate that the cardiotoxicity seen with osimertinib in clinical trials is largely recapitulated in preclinical models, and that osimertinib can directly induce CM death. These models may provide a foundation for further investigating mechanism of osimertinib-induced cardiotoxicity and interventions to mitigate it.