Potential Mechanism of Ponatinib-Induced Vascular Toxicity in CML
Posted: Wednesday, May 6, 2020
New research has shown that the third-generation tyrosine kinase inhibitor ponatinib significantly increased endothelial toxicity in vitro. The research, conducted by Damiana Pieragostino, PhD, of the University “G. d’Annunzio,” Chieti, Italy, and colleagues, also identified AKT/endothelial NOS and Notch-1 pathways as key targets in preventing ponatinib-associated vascular toxicity in patients treated for chronic myeloid leukemia (CML). Their findings were published in the Journal of Clinical Medicine.
The researchers exposed human umbilical endothelial cells to ponatinib, or a vehicle, in the presence or absence of the anti–Notch-1 antibody for exposure times of 0 to 72 hours. Analysis showed that the protein cargo of human umbilical endothelial cells treated with ponatinib triggered apoptosis and inhibited vasculature development.
The data showed the inhibition of tube formation using a branded complex protein mixture–based assay, upregulation of cleaved caspase-3, as well as downregulation of phosphorylated AKT and phosphorylated endothelial NOS. The signaling of ponatinib-induced vascular toxicity was identified, and it was found that ponatinib inhibited endothelial survival, reduced angiogenesis, and induced endothelial senescence and apoptosis via the Notch-1 pathway. Ponatinib induced endothelial toxicity in vitro.
Hyperactivation of Notch-1 in the vessels led to abnormal vascular development and dysfunction. By hyperactivating Notch-1 in the vessels, ponatinib exerted an “on-target off-tumor effect,” according to the investigators, which caused toxicity and may explain the drug’s vasculotoxicity. Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity, they noted.
“Strategies for endothelium-specific inhibition of Notch-1 such as anti-Notch antibodies, are warranted in order to protect the endothelium from ponatinib-induced vascular toxicity, without interfering with the anticancer effect of the drug,” the authors concluded.
Disclosure: The authors reported no conflicts of interest.