Abstract / Summary
Abstract Background Osimertinib is a standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer, but cancer therapy-related cardiac dysfunction (CTRCD) occurs in a subset of treated patients. The mechanisms underlying this patient-specific susceptibility remain unclear. We aimed to model osimertinib-associated CTRCD using patient-derived induced pluripotent stem cell-derived cardiomyocytes (pt-iPSC-CMs) and to investigate the involvement of AMP-activated protein kinase (AMPK)-related signaling. Methods pt-iPSC lines were established from peripheral blood mononuclear cells obtained from five patients with EGFR-mutated non-small cell lung cancer who had received osimertinib. Three patients who developed CTRCD were assigned to the CTRCD-positive group, and two patients who did not develop CTRCD were assigned to the CTRCD-negative group. The pt-iPSC clones were differentiated into cardiomyocytes, which were then treated with osimertinib. Cardiomyocyte contractile function was assessed by motion vector analysis using the SI8000 Live Cell Imaging System. The effects of osimertinib on the phosphorylation of EGFR, AMPK, and liver kinase B1 (LKB1) were evaluated by Western blotting. Metformin cotreatment was then tested to determine whether preservation of AMPK signaling could mitigate osimertinib-induced cardiomyocyte dysfunction. Results pt-iPSC-CMs from CTRCD-positive patients showed greater susceptibility to osimertinib-induced contractile dysfunction than those from CTRCD-negative patients. SuperPlot-based analysis showed that relative contraction velocity after treatment with 1.0 µM osimertinib was consistently lower in the CTRCD-positive group than in the CTRCD-negative group. Osimertinib suppressed EGFR phosphorylation in both groups, whereas phosphorylation of AMPK and LKB1 was selectively reduced in CTRCD-positive pt-iPSC-CMs. In these cardiomyocytes, metformin cotreatment at 0.1 and 0.3 mM significantly attenuated the reduction in AMPK phosphorylation without affecting osimertinib-induced suppression of EGFR phosphorylation. Functionally, 0.1 mM metformin significantly mitigated the osimertinib-induced decline in contraction velocity. Conclusions pt-iPSC-CMs recapitulated, at least in part, patient-specific susceptibility to osimertinib-associated CTRCD. Selective impairment of AMPK-related signaling, accompanied by reduced LKB1 phosphorylation, may contribute to this vulnerability. These findings highlight AMPK-related signaling as a potential contributor to osimertinib-induced contractile dysfunction and a candidate target for cardioprotective strategies in susceptible patients.