Key Findings
Research published in Cardio-Oncology on 5 October 2026 demonstrates that patient-derived induced pluripotent stem cell (iPSC) cardiomyocytes can recapitulate individual susceptibility to osimertinib-induced contractile dysfunction. The study identified that while osimertinib suppresses EGFR phosphorylation across all subjects, the reduction of AMPK and LKB1 phosphorylation occurs selectively in patients who develop cancer therapy-related cardiac dysfunction (CTRCD).
Technical Details
The research team, led by Sho Mitsuya and colleagues, utilized peripheral blood mononuclear cells from five patients with EGFR-mutated non-small cell lung cancer to establish iPSC lines. These were divided into a CTRCD-positive group (three patients) and a CTRCD-negative group (two patients). Using the SI8000 Live Cell Imaging System and motion vector analysis, the team found that cardiomyocytes from the CTRCD-positive group showed consistently lower relative contraction velocity after treatment with 1.0 µM osimertinib.
To investigate the mechanism, Western blotting was used to measure phosphorylation levels. The results showed that the energy-sensing pathway involving AMPK and LKB1 was impaired only in the susceptible cells. To test protection, the team applied metformin cotreatment at 0.1 and 0.3 mM. Metformin at 0.1 mM significantly mitigated the decline in contraction velocity and attenuated the reduction in AMPK phosphorylation without affecting the suppression of EGFR phosphorylation.
Background & Context
Osimertinib is a targeted therapy for EGFR-mutated non-small cell lung cancer, but it can trigger cardiac dysfunction in a subset of patients. The mechanism behind why some individuals are vulnerable while others are resilient has previously remained unclear.
Significance & Outlook
This study provides a personalized model to predict and prevent cardiotoxicity. By linking cellular response to the AMPK–LKB1 signaling pathway, the work points toward identifying at-risk patients before treatment begins. However, the authors note limitations, including a small sample size of five patients and the fact that findings are based on cell models rather than clinical patient data. Further broad validation is required for clinical application.
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