Effects of targeted lung cancer drugs on cardiomyocytes studied by atomic force microscopy

Area of Science:

• Cardiology
• Oncology
• Biophysics

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial targeted therapies for non-small cell lung cancer (NSCLC).
• Cardiac adverse events (AEs) are frequent complications of EGFR-TKI treatment, yet the underlying mechanisms remain unclear.
• Understanding the cellular effects of EGFR-TKIs on cardiomyocytes is essential for mitigating cardiac toxicity.

Purpose of the Study:

• To investigate the impact of EGFR-TKIs on the physical and mechanical properties of cardiomyocytes.
• To correlate drug-induced cellular changes with known clinical cardiac adverse events.
• To compare the cardiotoxic potential of gefitinib, afatinib, and osimertinib at the cellular level.

Main Methods:

• Utilized atomic force microscopy (AFM) to quantitatively assess cardiomyocyte physical properties.
• Measured cell height, adhesion, Young's modulus, and contraction/relaxation dynamics.
• Analyzed the effects of varying concentrations of gefitinib, afatinib, and osimertinib on cardiomyocytes.

Main Results:

• Significant alterations in cardiomyocyte mechanical properties (height, adhesion, Young's modulus, contraction/relaxation) were observed.
• These biophysical changes correlated strongly with clinical manifestations of cardiac AEs, including hypertrophy, QT prolongation, atrial fibrillation, reduced ejection fraction, and heart failure.
• Osimertinib exhibited the most pronounced effects at low concentrations, while gefitinib's impact increased with concentration, and afatinib showed the least effect.

Conclusions:

• AFM provides a novel cellular-level method to evaluate drug-induced cardiotoxicity.
• The study elucidates the physical basis of EGFR-TKI-associated cardiac AEs.
• This approach can aid in screening potential cancer therapeutics for cardiotoxic liabilities and understanding their mechanisms of action.