Abstract P041: A Novel Preclinical Strategy for Identifying Cardiotoxic Kinase Inhibitors and Mechanisms of Cardiotoxicity

Abstract

Rationale: 1) Despite intense interest in strategies to predict which tyrosine kinase inhibitor (TKI) cancer therapeutics may be associated with cardiotoxicity, current approaches are inadequate. 2) Sorafenib is a TKI of concern since it inhibits growth factor receptors and Raf-1/B-Raf, kinases that are upstream of ERKs and signal cardiomyocyte survival in the setting of stress. Objectives: 1) Explore the potential use of zebrafish as a pre-clinical model to predict cardiotoxicity. 2) Determine whether sorafenib has associated cardiotoxicity and, if so, define the mechanisms. Methods and Results: We find that the zebrafish model is readily able to discriminate a TKI with little or no cardiotoxicity (gefitinib) from one with demonstrated cardiotoxicity (sunitinib). Sorafenib, like sunitinib, leads to cardiomyocyte apoptosis, contractile dysfunction and ventricular dilatation in zebrafish. In cultured rat cardiomyocytes, sorafenib induces cell death. This can be rescued by adenovirus-mediated gene transfer of constitutively active MEK1 which restores ERK activity even in the presence of sorafenib. While growth factor-induced activation of ERKs requires Raf, α-adrenergic-induced activation of ERKs does not. Consequently, activation of α-adrenergic signaling virtually abrogates sorafenib-induced cell death. Consistently, inhibition of α-adrenergic signaling with prazosin augments sorafenib-induced contractile dysfunction in zebrafish. Conclusions: 1) Zebrafish may be a valuable pre-clinical tool to predict cardiotoxicity. 2) We identify a here-to-fore unknown pathway that bypasses Raf to activate ERKs, thereby limiting sorafenib cardiotoxicity. Importantly, given that the majority of men over the age of 60 have prostatic hypertrophy, for which α-adrenergic antagonists are the primary therapy, our findings suggest the consequences of the concomitant use of these agents with sorafenib should be explored.