Abstract
Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation–contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.
Highlights
Tyrosine kinase inhibitors (TKIs) constitute a class of cancer therapeutics, many of which are known to cause cardiotoxicity as a major adverse event
Since the reports of trastuzumab-induced toxicity, several additional targeted cancer therapeutics have been classified as cardiotoxic, observations that have contributed to the emergence of a new research field, cardio-oncology (Albini et al, 2010; Bellinger et al, 2015)
Previous studies have shown that TKI-related cardiotoxicity, as seen with trastuzumab, is mostly due to the targeting of pathways that are shared between malignancies and cardiovascular cells (De Keulenaer et al, 2010; Bellinger et al, 2015)
Summary
Tyrosine kinase inhibitors (TKIs) constitute a class of cancer therapeutics, many of which are known to cause cardiotoxicity as a major adverse event. Reported cardiotoxicities include heart failure, cardiomyopathy, conduction abnormalities, QT prolongation, and myocardial injury. The most common toxicity is systolic dysfunction or cardiomyopathy, potentially leading to heart failure, which is most likely mediated through direct toxicity of cardiomyocytes (Albini et al, 2010; Eschenhagen et al, 2011; Force and Kolaja, 2011; Raschi and De Ponti, 2012; Ewer and Ewer, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
