Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy

Abstract

// Xiao-Qiu Li 1, * , Jia-Tao Liu 1, 3, * , Lu-Lu Fan 1 , Yu Liu 1 , Liang Cheng 1 , Fang Wang 1 , Han-Qing Yu 1 , Jian Gao 3 , Wei Wei 2 , Hua Wang 1 , Guo-Ping Sun 1 1 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China 2 Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China 3 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China * These authors contributed equally to this work Correspondence to: Hua Wang, e-mail: wanghua@ahmu.edu.cn. Guo-Ping Sun, e-mail: sungp@ahmu.edu.cn. Keywords: lung cancer, exosomes, gefitinib, cisplatin, autophagy Received: November 03, 2015      Accepted: March 06, 2016      Published: March 25, 2016 ABSTRACT Several clinical trials indicate that concurrent administration of tyrosine kinase inhibitors (TKIs, such as gefitinib or erlotinib) with chemotherapy agents fails to improve overall survival in advanced non-small cell lung cancer (NSCLC) patients. However, the precise mechanisms underlying the antagonistic effects remain unclear. In the present study, we investigated the role of exosomes in the antagonistic effects of concurrent administration of chemotherapy and TKIs. Exosomes derived from gefitinib-treated PC9 cells (Exo-GF) decreased the antitumor effects of cisplatin, while exosomes derived from cisplatin-treated PC9 cells (Exo-DDP) did not significantly affect the antitumor effects of gefitinib. Additionally, inhibition of exosome secretion by GW4869 resulted in a modest synergistic effect when cisplatin and gefitinib were co-administered. Furthermore, Exo-GF co-incubation with cisplatin increased autophagic activity and reduced apoptosis, as demonstrated by an upregulation of LC3-II and Bcl-2 protein levels and downregulation of p62 and Bax protein levels. Thus, the antagonistic effects of gefitinib and cisplatin were mainly attributed to Exo-GF, which resulted in upregulated autophagy and increased cisplatin resistance. These results suggest that inhibition of exosome secretion may be a helpful strategy to overcome the antagonistic effects when TKIs and chemotherapeutic agents are co-administered. Before administering chemotherapy, introducing a washout period to completely eliminate TKI-related exosomes, may be a better procedure for administering chemotherapy and TKIs.