Patient-Derived Heart Cells Reveal Susceptibility to Osimertinib-Induced Cardiac Dysfunction

Osimertinib, a targeted therapy widely used against EGFR-mutated non-small cell lung cancer, can trigger cancer therapy-related cardiac dysfunction in a subset of treated patients. Why some individuals develop this cardiotoxicity while others do not has remained unclear. A new study published in Cardio-Oncology on 5 October 2026 reports that heart muscle cells grown from patients’ own stem cells reproduce this individual susceptibility in the laboratory, and points to impaired AMPK–LKB1 signaling as a possible mechanism.

The research team, led by Sho Mitsuya and colleagues, established induced pluripotent stem cell lines 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 cancer therapy-related cardiac dysfunction formed the CTRCD-positive group, while two patients who did not develop it formed the CTRCD-negative group. These patient-derived iPSC clones were then differentiated into cardiomyocytes and treated with the drug, creating a personalized model of each patient’s cardiac response.

Contractile function was assessed by motion vector analysis using the SI8000 Live Cell Imaging System. Cardiomyocytes 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, indicating that the cells retained a memory of their donor’s clinical vulnerability.

To probe the underlying signaling, the researchers used Western blotting to measure phosphorylation of EGFR, AMP-activated protein kinase (AMPK), and liver kinase B1 (LKB1). Osimertinib suppressed EGFR phosphorylation in cardiomyocytes from both groups, showing that the drug hit its molecular target regardless of susceptibility. In contrast, phosphorylation of AMPK and LKB1 was selectively reduced only in the CTRCD-positive cells, suggesting that impairment of this energy-sensing pathway distinguishes vulnerable patients from resilient ones.

The team then tested whether preserving AMPK signaling could protect the cells. Metformin cotreatment at 0.1 and 0.3 mM significantly attenuated the reduction in AMPK phosphorylation in the susceptible cardiomyocytes without affecting osimertinib-induced suppression of EGFR phosphorylation, meaning the protective effect did not compromise the drug’s anticancer target. Functionally, 0.1 mM metformin significantly mitigated the osimertinib-induced decline in contraction velocity.

The authors conclude that patient-derived iPSC cardiomyocytes recapitulated, at least in part, patient-specific susceptibility to osimertinib-associated cardiac dysfunction, and that selective impairment of AMPK-related signaling, accompanied by reduced LKB1 phosphorylation, may contribute to this vulnerability. They emphasize that AMPK-related signaling is a potential contributor to the contractile dysfunction and a candidate target for cardioprotective strategies in susceptible patients.

Several limitations frame these findings. The study involved only five patients, with three in the positive group and two in the negative group, so the observations are exploratory rather than definitive. The work was conducted in cell models, and metformin’s protective effect was demonstrated in cultured cardiomyocytes, not in patients. The authors note that the cells recapitulated susceptibility only partially, and clinical application would require much broader validation. The article was also shared early as a peer-reviewed accepted version subject to further edits before the final Version of Record.

Even so, the study offers a concrete step toward predicting and preventing a feared side effect of a mainstay lung cancer therapy. By showing that a patient’s cellular response can be modeled in a dish and linked to a specific signaling pathway, the work suggests a route toward identifying patients at risk of cardiac dysfunction before treatment begins, and toward testing cardioprotective combinations that leave the anticancer activity of osimertinib intact.

Subject of Research: Patient-derived iPSC cardiomyocytes modeling individual susceptibility to osimertinib-induced cardiac dysfunction via impaired AMPK–LKB1 signaling

Article Title: Differential susceptibility to osimertinib-induced contractile dysfunction involves AMPK–LKB1 signaling impairment in patient-derived iPSC cardiomyocytes

Article References: Mitsuya, S., Morihara, H., Funamoto, T., Tamura, Y., Ikeda, S., Takai, S., & Fujisaka, Y. (2026). Differential susceptibility to osimertinib-induced contractile dysfunction involves AMPK–LKB1 signaling impairment in patient-derived iPSC cardiomyocytes. Cardio-Oncology. https://doi.org/10.1186/s40959-026-00586-9

Image Credits: AI Generated

DOI: 10.1186/s40959-026-00586-9

Keywords: osimertinib, cardiotoxicity, EGFR-mutated non-small cell lung cancer, induced pluripotent stem cells, cardiomyocytes, AMPK, LKB1, metformin, cancer therapy-related cardiac dysfunction, contractile dysfunction, cardio-oncology, Differential