Extracellular vesicles shed from gefitinib‐resistant nonsmall cell lung cancer regulate the tumor microenvironment |
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| Authors: | Do‐Young Choi Sungyong You Jae Hun Jung Jae Cheol Lee Jin Kyung Rho Kye Young Lee Michael R. Freeman Kwang Pyo Kim Jayoung Kim |
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| Affiliation: | 1. Department of Applied Chemistry, College of Applied Science, Kyung Hee University, , Yongin, Republic of Korea;2. Departments of Surgery and Biomedical Sciences, Division of Cancer Biology and Therapeutics, Samuel Oschin Comprehensive Cancer Institute, Cedars?Sinai Medical Center, , Los Angeles, CA, USA;3. Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, , Seoul, Korea;4. Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, , Seoul, Korea;5. Department of Internal Medicine, Konkuk University School of Medicine, , Seoul, Korea;6. Boston Children's Hospital, Harvard Medical School, , Boston, MA, USA;7. Departments of Surgery and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, , Boston, MA, USA |
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| Abstract: | Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs), including gefitinib, are the first‐line treatment of choice for nonsmall cell lung cancer patients who harbor activating EGFR mutations, however, acquired resistance to EGFR‐TKIs is inevitable. The main objective of this study was to identify informative protein signatures of extracellular vesicles (EV) derived from gefitinib‐resistant nonsmall cell lung cancer cells using proteomics analysis. Nano‐LC–MS/MS analysis identified with high confidence (false discovery rate < 0.05, fold change ≥2) 664 EV proteins enriched in PC9R cells, which are resistant to gefitinib due to EGFR T790M mutation. Computational analyses suggested components of several signal transduction mechanisms including the AKT (also PKB, protein kinase B)/mTOR (mechanistic target of rapamycin) pathway are overrepresented in EV from PC9R cells. Treatment of recipient cells with EV harvested from PC9R cells increased phosphorylation of signaling molecules, and enhanced proliferation, invasion, and drug resistance to gefitinib‐induced apoptosis. Dose‐ and time‐dependent pharmaceutical inhibition of AKT/mTOR pathway overcame drug resistance of PC9R cells and those of H1975 exhibiting EGFR T790M mutation. Our findings provide new insight into an oncogenic EV protein signature regulating tumor microenvironment, and will aid in the development of novel diagnostic strategies for prediction and assessment of gefitinib resistance. |
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| Keywords: | AKT Cell biology Extracellular vesicles mTOR signaling pathway Nonsmall cell lung cancer |
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