Protective effects of metformin against ponatinib-induced toxicity in iPSC-derived cardiomyocytes

Aims: Ponatinib is currently considered the most effective treatment for patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who develop resistance or intolerance to first- and second-line therapy, particularly those with T315I "gatekeeper" mutation in BCR-ABL. However, ponatinib is also one of the most cardiotoxic tyrosine kinase inhibitors (TKIs), with toxicity stemming from a combination of contractile dysfunction and inflammatory effects. Our goal was to model and investigate this toxicity in human-induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CMs) and to evaluate whether metformin, a clinically well-tolerated antidiabetic drug with known cardioprotective potential via AMPK pathway activation in various pathologies, can mitigate the damage.