Abstract
Background: The advent of tyrosine kinase inhibitor (TKI) targeted therapy revolutionized the treatment of chronic myelogenous leukemia (CML) patients, leading to a significant impact on remission rates and overall survival. However, cardiotoxicity associated with these targeted therapies put the cancer survivors at greater risk. Ponatinib is an example shown unexpected wide spectrum of cardiotoxic complications which limits its clinical applications. A newly designed 4 th -generation tyrosine kinase inhibitor PF114 having better target spectra in CML, could be a potential alternative to ponatinib. But the cardiotoxic potential of PF114 is not yet fully understood. Objectives: The objectives of the present study were to compare cardiotoxicity of ponatinib with PF114. Methods: In this study, we employed zebrafish transgenic BNP reporter line that expresses luciferase under control of the nppb promoter ( nppb : F-Luciferase) to compare cardiotoxic potential of TKIs. We also exploited NRVMs to explore cardiotoxic mechanism associated with ponatinib and PF114. Results: We observed that increasing dose of PF114 showed minimal induction of the BNP reporter compared to ponatinib. PF114 did not reduce the ventricular fractional shortening in zebrafish as compared to ponatinib. Consistently, in cultured rat cardiomyocytes, PF114 could not reiterate the same cardiotoxic effect of ponatinib as depicted by cell viability and TUNEL assay. Mechanistically, PF114 has shown no effects on essential prosurvival AKT and ERK signaling pathway while ponatinib is known to exerts its cardiotoxic effects by their inhibition. Additionally, the allosteric tyrosine kinase inhibitor ABL001(Asciminib) in combination with PF114 depicts less pronounced cardiotoxic effects than ponatinib in similar settings. Conclusions: This study provides further rationale to utilize zebrafish for the prediction of cardiotoxicity of anticancer drugs. The comparative cardiotoxicity of ponatinib and PF114 suggest that PF114 is a significantly less cardiotoxic analogue and safer treatment option than ponatinib for CML patients harboring BCR/ABL-T315I “gatekeeper” mutation.
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