PROJECT SUMMARY (Project 1) In the past two decades, the recognition that aberrant activation of kinases plays a critical role in the pathogenesis of cancers, has stimulated efforts to develop kinase inhibitors for therapy. However, kinase inhibitors (KI) can lead to adverse cardiovascular effects, either due to the inhibition of the intended kinase target (“on-target”) or another kinase (“off-target”). Existing needs in the field include understanding the paradigm of “on-target” versus “off-target” and the need for generating a pre-clinical model to model drug toxicity in patients. Project 1 of this PPG will focus on establishing pre-clinical models of covalent kinase inhibitor-associated cardiotoxicity and attempt to understand the underlying mechanisms of toxicity. Specifically, ibrutinib (a first in- class covalent KI) is associated with arrhythmia (especially atrial fibrillation), representing a unique and novel toxicity. In Aim 1, we will utilize cell-based and novel genetic tools to examine that ibrutinib cardiotoxicity is mediated via an “off-target” kinase, C-terminal Src Kinase (CSK). In Aim 2 we will use mouse models to show a critical role for CSK in cardiotoxicity and test an additional hypothesis that ibrutinib treatment leads to cardiac remodeling which further contributes to electrophysiologic effects. Aim 3 will use our clinical/pharmacovigilance databases to corroborate our pre-clinical findings to clinical space. There is considerable synergy with Project 2 of this PPG (led by Dr. Joseph Wu), which seeks to identify risk factors for ibrutinib-associated cardiotoxicity, as well as Project 3 (PI: Dr. Mark Mercola), which hopes to develop cardioprotective medications for KI-associated cardiotoxicity. Although the 3 projects will focus on ibrutinib and other BTK inhibitors, the platforms created can be applied to the many novel covalent and noncovalent KI that are being approved in oncology.