Iron Oxide Nanoparticles Synergize with Erlotinib to Suppress Refractory Non-Small Cell Lung Cancer Cell Proliferation Through the Inhibition of ErbB/PI3K/AKT and PTEN Activation

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib and gefitinib, are currently approved for the management of NSCLC. However, primary and acquired resistances to EGFR-TKIs are the major obstacles in the treatment of NSCLC. These resistances have been associated with the development of secondary mutations in EGFR or continued oncogenic signaling despite TKI treatment. In this study, NSCLC cells with wild-type EGFR, A549, H460, H358, H157 which do not respond to EGFR-TKIs, were used. We investigated whether a combination therapy of erlotinib plus iron oxide nanoparticles (IONPs) could sensitize NSCLC cells to erlotinib-induced cancer inhibition. In the 4 NSCLC cells investigated, erlotinib and IONPs combination therapy obviously inhibited NSCLC proliferation in vitro and in vivo, compared with erlotinib treatment alone. This effect was not dependent on erlotinib dose. Activation of ErbB3 was observed in these refractory NSCLC cells. Combined with IONPs, erlotinib could block ErbB3 activity and induce the expression of PTEN, which in turn inhibited the downstream PI3K-AKT signaling pathway. These data demonstrate the therapeutic potential of biocompatible IONPs in combination with EGFR-TKIs in NSCLC, thus expanding and repurposing the current therapy for NSCLC.