Abstract 14022: Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity

Abstract

Introduction: Second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAE) in patients with Philadelphia-chromosome positive (Ph+) leukemia. Hypothesis: We hypothesized that second and third generation BCR-ABL1 TKIs may cause CVAE through activation of Rho-associated protein kinase (ROCK). Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3, 5-37]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro , which could contribute to CVAE. Results: Patients receiving second and third generation TKIs had 1.6-fold greater ROCK activity compared to both patients receiving imatinib and control patients. Elevated ROCK activity was associated with increased incidence of CVAE in Ph+ leukemia patients (Figure). In endothelial cells in vitro , we found that dasatinib and ponatinib treatment lead to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib leads to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment lead to phospho-inhibition of endothelial nitric oxide synthase (eNOS) and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and eNOS-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAE in patients receiving BCR-ABL1 TKIs. ROCK inhibition may be a promising approach in reducing the incidence of CVAE associated with second and third generation BCR-ABL1 TKIs.