Ponatinib-Induced Cardiomyocyte Toxicity: Dark Side of the Integrated Stress Response

Ponatinib is a small molecule tyrosine kinase inhibitor (TKI) used to treat certain leukemias driven by the BCR-ABL oncogene.The use of ponatinib is limited by major cardiovascular toxicities.Yan et al 1 elucidate a novel mechanism of ponatinib-induced cardiomyocyte toxicity involving the integrated stress response.The driver mutation in chronic myeloid leukemia (CML) and Philadelphia chromosomepositive acute lymphoblastic leukemia (ALL) is a reciprocal translocation between chromosomes 9 and 22 resulting in the BCR-ABL fusion protein, a constitutively active tyrosine kinase.Over the past 2 decades, TKIs with activity against BCR-ABL have transformed the treatment of these malignancies.However, resistance to treatment can develop through multiple mechanisms including acquisition of the T315I mutation in BCR-ABL.Ponatinib is a third-generation BCR-ABL TKI that retains potent activity against T315I BCR-ABL.Ponatinib additionally inhibits other tyrosine kinases including receptors for FGF, VEGF, and PDGF.The most common and serious cardiovascular toxicity of ponatinib is thrombotic arterial and venous occlusive events, which can precipitate fatal myocardial infraction, stroke, and pulmonary embolism 2 .These vaso-occlusive events resulted in the temporary withdrawal of ponatinib from the market a decade ago until monitoring guidelines could be formulated.Other less frequent cardiovascular complications have been reported including arrhythmias, hypertension, and heart failure, the latter being the focus of Yan et al.