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Trastuzumab, but not pertuzumab, inhibits autophagy and enhances ROS production in human cardiomyocytes; Implications of autophagy in trastuzumab-induced cardiotoxicity

Thursday, September 17, 2015 — Poster Session II

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • N Mohan
  • Y Shen
  • WJ Wu


Autophagy is basic catabolic cellular process which is essential for maintaining cellular homeostasis during nutrient starved and stress conditions. Even though autophagy is altered in various cardiovascular diseases including cardiomyopathy and heart failure, its precise role in normal and pathological heart remains ambiguous. Trastuzumab is a humanized monoclonal antibody approved for treatment of HER2-positive breast cancer. Trastuzumab treatment has been shown to induce considerable cardiotoxicity, mechanism of which remains largely unclear. In this study, we investigated the role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity using human cardiomyocytes and mice models. Results divulged that expression levels of LC3I/II were markedly decreased in cardiomyocytes after 24 and 48 h of trastuzumab treatment. Autophagosome associated proteins were predominantly downregulated indicating that formation of autophagosomes is substantially compromised. We further demonstrated that autophagy inhibition by trastuzumab resulted in enhance in reactive oxygen species production and oxidative stress. Surprisingly, we also noticed that pertuzumab therapy fail to modulate autophagy in human cardiomyocytes and ROS production remain unchanged following pertuzumab treatment. Investigations of molecular mechanisms reveal that trastuzumab activated mTOR, which in turn phosphorylated Ulk1 at Ser 757 resulting in suppression of autophagy. Collectively, these data indicate that autophagy plays a beneficial role in normal cardiac tissues by preventing the accumulation of abnormal proteins or damaged organelles. However, trastuzumab treatment inhibits the autophagy via mTOR/Ulk 1 pathway, resulting in cardiotoxicity and cardiomyopathy.

Category: Cancer Biology