Dasatinib causes pulmonary endothelial damage and aggravates pulmonary hypertension - 21/12/15

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, an orally bioavailable dual Src/Bcr-Abl tyrosine kinase inhibitor (TKI) used in the treatment of chronic myelogenous leukaemia (CML). Today, key questions remain regarding the long-term evolution of dasatinib-induced PAH and the mechanism(s) involved.

Here, we report major improvements and some cases of complete normalization of clinical, functional, and hemodynamic status 4–54 months after dasatinib withdrawal–and PAH therapy in some cases–in a well-characterized cohort of 18 incident cases of dasatinib-induced PAH. In contrast to chronic imatinib treatment, we demonstrate that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that rats pretreated with dasatinib, but not with imatinib, exhibit increased susceptibility to experimental pulmonary hypertension (PH). Furthermore, we found significant elevations of markers of endothelial dysfunction or damage in the serum of CML patients treated with dasatinib when compared with CML patients treated with imatinib. These in vivo observations were replicated in vitro, with a dose-dependent induction of pulmonary endothelial cell apoptosis of cultured pulmonary endothelial cells with dasatinib, but not with imatinib, a phenomenon mediated through production of reactive oxygen species (ROS) and induction of endoplasmic reticulum (ER) stress and not dependent of Src kinase inhibition.

Collectively, we show that dasatinib causes pulmonary endothelial damage and aggravates PH through production of ROS and induction of chronic ER stress.