Role of TKIs on activating cardiac fibroblasts
Date
2024
Authors
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Publisher
University of Delaware
Abstract
Non-specific anticancer drugs show a wide range of adverse effects, including irreversible cardiotoxicity. To limit such events, tyrosine kinase inhibitors (TKIs) are designed to specifically inhibit the receptor tyrosine kinases (RTKs) that are upregulated in ~70% of cancers. However, TKIs can still cause reversible cardiotoxicities, suggesting that they do not compromise heart function by causing considerable cardiomyocyte death. Thus, there is an increasing effort to understand the role of non-cardiomyocytes, particularly cardiac fibroblasts (CF), in drug-induced cardiotoxicity. Previous studies on animal (pharmacological and genetic) models and clinical data show conflicting results on TKI-induced CF-specific cardiotoxicities. To address this, we used the human induced pluripotent stem cell (iPSC) platform to derive cardiac fibroblasts, which can bypass the inherent physiological differences between human and animal models. We selected four widely used TKIs (sorafenib, sunitinib, cabozantinib, and lapatinib) in this study. Our data indicated that while sorafenib was the most cytotoxic to CFs, it showed a tendency to activate CF at low concentrations. However, sunitinib and cabozantinib did not activate the CFs. Lapatinib, on the other hand, showed CF activation, expressing higher α-smooth muscle actin (αSMA) at the protein level, despite no CF-activation at the gene level. In search for the underlying mechanism of TKI-induced CF-activation, we assessed the expressions of several circular RNAs (circRNAs) upon TGFβ and sorafenib exposure that are implicated in fibrosis and cardiac dysfunction. We observed no change of circRNA (circNFIX, circZNF609, circHIPK3, and circPVT1) expression on activation of CFs. Finally, we were able to reduce CF-activation marker gene expression by knocking down circZNF609, suggesting the potential of targeting circRNAs in TKI-induced cardiac dysfunction. In summary, this study shows that the iPSC-CF provides a new modeling platform to identify potential therapeutic targets in TKI-induced cardiotoxicity and circRNAs might be mediating CF-activation in such scenarios.
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Keywords
Cardiac fibroblast activation, Circular RNA, iPSC, Reversible cardiotoxicity, Tyrosine kinase inhibitors