Peptide Ligand of the Epidermal Growth Factor Receptor for Sensitizing Lung Cancer Cells to Gefitinib

Background By the end of 2016, 13.3% and 26.5% of new lung cancer diagnoses and deaths respectively is anticipated in the United States. Effective treatment of lung cancer is, however, hampered by adverse effects and the rapid acquisition of resistance to therapies. The epidermal growth factor receptor (EGFR) is an important lung cancer target. However, resistance to EGFR‐targeted therapies such as the receptor tyrosine kinase inhibitors, RTKIs (e.g. gefitinib) limits favorable long‐term therapeutic outcomes. The current study investigates the sensitization of EGFR‐expressing, gefitinib‐resistant lung cancer cells by the lung surfactant protein D (SPD). Methods Resazurin reduction‐based cell viability assay was performed to validate resistance to gefitinib in a panel of seven non‐small cell lung cancer (NSCLC) cells. Sensitization studies with single and combination treatments of SPD and geftinib were carried out in H1573 cells. The effect of SPD‐mediated H1573 sensitization to gefitinib on EGFR signaling examined by western blot. Results Gefitinib inhibited lung cancer cell viability in HCC827, H661, A549, H460, H1299, H1975, and H1573 [IC 50 = 0.06±0.01 μM, 4.82±0.77 μM, 5.44±0.16 μM, 5.88±1.02 μM, 7.38±0.75 μM, 7.65±0.58 μM, 23.61±2.21 μM respectively]. SPD (0.5 μg/mL) inhibited H1573 cell viability (43.78±1.72 %), and significantly sensitized the cells to 5.0 μM gefitinib (13.16±0.82 % cell viability). SPD and gefitinib mediated EGFR degradation (phospho‐EGFR Tyr 1045) and inhibited Ras signaling (phospho‐EGFR Tyr 1086) in H1573 cells. Conclusion The lung surfactant protein D (SPD) was effective in sensitizing highly resistant H1573 cells to gefitinib treatment by inhibiting EGFR activating signaling. SPD may represent a viable candidate for adjunctive therapy in chemo‐refractory lung cancer overexpressing EGFR.