Abstract 4370530: Protective Mechanisms Against Cardiac Toxicity of the EGFR Tyrosine Kinases Inhibitor Osimertinib

Introduction: Targeted therapies with Tyrosine Kinase Inhibitors (TKIs) have drastically improved the survival of cancer patients. However, long term exposure to TKIs has been associated with severe cardiac adverse events impairing patient survival and life quality, and limiting treatment options. Osimertinib is an EGFR tyrosine kinase inhibitor currently used as first line treatment for the EGFR mutated metastatic form of non-small cell lung cancer (NSCLC). Osimertinib has been associated with a ~5% incidence of cardiac toxicity in treated patients, including the development of severe heart failure and arrhythmias. Therefore, there is an unmet clinical need to identify protective mechanisms with the aim of improving quality of life and survival of patients with metastatic NSCLC. The cardioprotective effect of MAPK pathway has been previously described for cardiac ischemic disease. Hypothesis: We postulate that inhibiting MAPK signaling could confer a cardioprotective effect against the cardiac toxicity of the EGFR inhibitor Osimertinib. Methods: For this study we used Osimertinib as models of cardiac toxicity. We performed in vitro functional assays to evaluate the cardiotoxicity and cardiac protection using human iPSC-cardiomyocytes (hiPSC-CMs). Cardiotoxicity was evaluated by impairment of cardiomyocyte contractile function during Osimertinib treatment. The cardiac protection was evaluated by restoration of contractile function post-inhibition of MAPK pathway with commercially available MAPK inhibitors. Results: Osimertinib showed significant decrease in contractile function of cardiomyocytes. The simultaneous treatment with the EGFR inhibitor and MAPK pathway inhibitors significantly improved the contractile function of the cardiomyocytes. Conclusion: Our study shows inhibiting MAPK signaling protects against the cardiac toxicity associated with the EGFR inhibitor Osimertinib in human cardiomyocytes. These findings suggest that inhibiting MAPK might mitigate cardiac toxicity in patients undergoing drug treatment for metastatic NSCLC.