Involvement of kallikrein‐PAR2‐proinflammatory pathway in severe trastuzumab‐induced cardiotoxicity

Abstract

Trastuzumab-induced cardiotoxicity interferes with continued treatment in approximately 10% of patients with ErbB2-positive breast cancer, but its mechanism has not been fully elucidated. In this study, we recruited trastuzumab-treated patients with ≥30% reduction in left ventricular ejection fraction (SP) and noncardiotoxic patients (NP). From each of these patients, we established three cases of induced pluripotent stem cell-derived cardiomyocytes (pt-iPSC-CMs). Reduced contraction and relaxation velocities following trastuzumab treatment were more evident in SP pt-iPSC-CMs than NP pt-iPSC-CMs, indicating the cardiotoxicity phenotype could be replicated.Differences in ATP production, reactive oxygen species, and autophagy activity were observed between the two groups. Analysis of transcripts revealed enhanced kal-likrein5 expression and pro-inflammatory signaling pathways, such as interleukin-1β, in SP pt-iPSC-CMs after trastuzumab treatment. The kallilkrein5-protease-activated receptor 2 (PAR2)-MAPK signaling pathway was more activated in SP pt-iPSC-CMs, and treatment with a PAR2-antagonist suppressed interleukin-1β expression. Our data indicate enhanced pro-inflammatory responses through kallikrein5-PAR2 signaling and vulnerability to external stresses appear to be the cause of trastuzumabinduced cardiotoxicity in SP.

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology

“…Experiments conducted on iPSC‐CMs showed that the direction of this process might depend on the drug concentration. At a low dose of 1 μM, TZM suppressed the autophagy, whereas at higher doses of 10 μM a significant augmentation of this process was found, which is linked by the authors of this study with higher production of ROS upon 10 μM of TZM [ 437 ]. Further transcriptomic analysis of cells exposed to lower doses of TZM showed that it induces an inflammation-like state, as evidenced according to upregulated expression levels of IL1β , TNFRSF8 , and PTGS1, oversecreted kallikrein 5 (KLK5) and 8 (KLK8), and increased production of KLK5/KLK8 substrate, PAR2.…”

“…Moreover, TZM promoted the phosphorylation of ERK1/2 and JNK. Considering the role of these kinases in proinflammatory signals arising in response to PAR2 activation [ 438 , 439 ], their contribution to the formation of the inflammatory milieu in TZM-treated cardiomyocytes is indisputable [ 437 ]. TZM-driven inflammatory conditions confirmed research on rabbits where the drug caused myocardium infiltration with lymphocytes and macrophages [ 440 ].…”