Background: Human epidermal growth factor receptor-2 (HER2) related signaling pathways are important to the survival of breast cancer cells, making HER2 an effective target for the treatment of certain breast cancers. However, HER2 is also important in cardiac development and cardiomyocyte survival, proliferation and stress adaption. Cardiotoxicity is a serious side effect of drugs that target HER2, including trastuzumab and lapatinib. In this study, we systematically compared the effects of these two drugs on human embryonic stem cell (hESC)-derived cardiomyocytes.
Methods: Cardiomyocytes were generated from hESC by stimulation with Activin A, Wnt3a and Bone Morphogenetic Protein 4 pathways. Matrigel was used to recoat and trap the differentiating cells to augment the yield of cardiomyocytes. We studied the effects of trastuzumab and lapatinib on cell injury, apoptosis, mitochondrial function, DNA synthesis, calcium handling and HER2 surface expression and phosphorylation in hESC-derived cardiomyocytes.
Results: Both trastuzumab and lapatinib induce apoptosis, impair mitochondrial membrane potential and block neuregulin-1 stimulated cardiomyocyte proliferation. At clinically relevant concentrations, trastuzumab displayed more pronounced effects on calcium handling. Trastuzumab also decreased HER2 protein levels and increased HER2 mRNA levels, while lapatinib did not. These differences may explain clinical differences between the two agents in their cardiac effects.
Conclusions: While trastuzumab and lapatinib have similar dose-dependent effects on many readouts of cellular physiology, they differ remarkably in calcium handling and HER2 expression. These results point to calcium handling and HER2 expression as possible mechanisms for the clinical differences in cardiotoxicity between these two agents. Combined with new technologies in generating induced pluripotent stem cells (iPSC), these results suggest a new approach to screen patient-specific iPSC-CM for cardiotoxicity to prospectively predict drug response and toxicity, and optimize drug selection in individual patients.
Keywords: Cardiac differentiation, cardiotoxicity, calcium cycling, trastuzumab, lapatinib, HER2, chemotherapy