No abstract

Background: Lung cancer patients with mutations in the epithelial growth factor receptor (EGFR) are treated with tyrosine kinase inhibitors (TKI) such as Erlotinib. Although resistance to EGFR-TKI is common, it is not known how biomechanical factors in the lung tumor microenvironment alters resistance. Alveolar epithelial cells experience 15% cyclic strain while increased tumor stiffness result in 40-fold decrease in cyclic strain. However, it is not known if cyclic mechanical strain alters the sensitivity of lung adenocarcinoma cells to EGFR-TKI. Mechanical stretch and silencing a membrane repair protein, myoferlin (MYOF), results in fluidization of the actin cytoskeleton. In this study we investigated how cyclic strain and silencing MYOF modulates EGFR expression and Erlotinib sensitivity in lung adenocarcinoma cells. Method: A Flexcell system was used expose human lung adenocarcinoma cells (A549 and H1299) to 0.2Hz cyclic strain (0-15%) for 72h. To knockdown MYOF expression, cells were treated with 30uM siRNA for 24h. Cells were expose to a range of Eroltinib concentrations and a MTT cell proliferation assay was used to determine the concentration require to reduce proliferation by 50% (i.e. IC50). Western blots and immunohistochemistry were used to quantify EGFR expression and localization. Result: Increasing the magnitude of cyclic strain caused a dramatic decrease in IC50 for A549 and H1299 cells. Similarly, silencing MYOF lead to a dramatic decrease in IC50 in A549 and H1299 cells. Cyclic strain and MYOF knockdown resulted in both increased EGFR expression and internalization. Conclusion: Low levels of cyclic strain in the lung tumor microenvironment lead to increased Erlotinib resistance and exposure to physiologic levels of cyclic strain initiates EGFR signaling and increases Erlotinib sensitivity. This highlights the need for modeling and characterizing the mechanics of the lung tumor microenvironment to investigate how cyclic strain and MYOF expression influence chemosensitivity to other cancer therapeutics.Background: Lung cancer is the leading cause of cancer related mortality among both women and men in the United States and worldwide.