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

BACKGROUND Second-and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph thorn ) leukemia. OBJECTIVES We hypothesized that second-and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). METHODS Peripheral blood mononuclear cells from 53 Ph thorn patients on TKIs and 15 control patients without Ph thorn leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up 1/4 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. RESULTS Patients receiving second-and third-generation TKIs had 1.6-fold greater ROCK activity compared with pa-tients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph thorn leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. CONCLUSIONS Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second-and third-generation BCR-ABL1 TKIs. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.