Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes

Abstract

Background Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Methods Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Results Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Conclusions Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity. Graphical Abstract

Insights into Drug Cardiotoxicity from Biological and Chemical Data: The First Public Classifiers for FDA Drug-Induced Cardiotoxicity Rank

“…Turning to manual annotations of compound MOA and/or targets, we found that cyclooxygenase inhibitors along with tyrosine kinase receptor inhibitors were the most significant annotations differentiating the various DICT concern categories (Table ); this is plausible given cyclooxygenase inhibition, besides reducing inflammation, can also lead to increased blood pressure while tyrosine kinase receptor inhibition can induce endoplasmic reticulum stress and inflammation in cardiomyocytes . In agreement with this, known targets of prostaglandin endoperoxide synthases (PTGS1 and PTGS2 genes, which encode cyclooxygenases COX-1 and COX-2) could significantly distinguish among most-, less-, and no-DICT concern categories (Table ).…”

Insights into Drug Cardiotoxicity from Biological and Chemical Data: The First Public Classifiers for FDA DICTrank

“…Turning to manual annotations of compound mechanisms of action and/or targets, we found that cyclooxygenase inhibitors 56 along with tyrosine kinase receptor inhibitors were the most significant annotations differentiating the various DICT concern categories (Table 3); this is plausible given cyclooxygenase inhibition, besides reducing inflammation, can also lead to increased blood pressure 57 while tyrosine kinase receptor inhibition can induce endoplasmic reticulum stress and inflammation in cardiomyocytes. 58 In agreement with this, known targets of prostaglandin endoperoxide synthases (PTGS1 and PTGS2 genes, which encode cyclooxygenases COX-1 and COX-2) could significantly distinguish among most-, less- and no-DICT concern categories (Table 3).…”

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

“…Though we did not specifically address the mechanism that stands behind activation of immunoproteasome subunit expression following the incubation with the MKIs, it is well established that non-constitutive proteasome expression is increased in various stress conditions including oxidative stress ( Johnston-Carey et al, 2015 ; Petersen and Zetterberg, 2016 ; Raynes et al, 2016 ; Wang et al, 2023 ). MKIs were demonstrated to induce various types of stress ( Wang et al, 2023 ). Specifically, sorafenib was shown to induce oxidative stress, endoplasmic reticulum stress and inflammation ( Rahmani et al, 2007 ; Wei et al, 2021 ; Wang et al, 2023 ).…”

“…MKIs were demonstrated to induce various types of stress ( Wang et al, 2023 ). Specifically, sorafenib was shown to induce oxidative stress, endoplasmic reticulum stress and inflammation ( Rahmani et al, 2007 ; Wei et al, 2021 ; Wang et al, 2023 ). Regorafenib was also shown to induce endoplasmic reticulum stress ( Sui et al, 2023 ), as well as the oxidative stress in colon cancer cells ( Yu et al, 2023 ).…”