The dual EGFR/HER2 inhibitor lapatinib confers functional protection from trastuzumab-induced cardiotoxicity. (A–D) HUVECs were exposed to trastuzumab with or without lapatinib for 24 h and the conditioned medium was added to CCC-HEH-2 cells and iPSC-CMs. (A) The Ca2+ content of CCC-HEH-2 cells measured by flow cytometry (n = 4). (B–D) The normalized survival rate, contraction amplitude, and beat rate of iPSC-CMs (n = 6 individuals). (E–J) Sprague Dawley rats were treated with saline, anti-HER2/neu antibody, lapatinib, or lapatinib plus anti-HER2/neu antibody for 4 weeks (n = 6 rats). (E) The schematic diagram of animal experiment. (F) Serum was analysed for PTX3 level by ELISA. (G) Cardiac function examined by echocardiography. (H) Organ index of the heart. (I and J) Heart sections were stained with P-EGFR (Y1068) and p-STAT3 (Y705) antibody by immunohistochemistry (n = 3 rats). Scale bar, 100 μm and 25 μm. The P-value was calculated by one-way ANOVA (Sidak test) or two-way ANOVA (Tukey’s test). NS, no significance; *P < 0.05, **P < 0.01, ***P < 0.001. Ctrl-Medium, Control medium; Tra-Medium, trastuzumab medium; Lapa-Medium, lapatinib medium; Lapa/Tra-Medium, lapatinib-plus-trastuzumab medium.
