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[ Title ]

- Inhibition of Oncogenic Epidermal Growth Factor Receptor Kinase Triggers Release of Exosome-like Extracellular Vesicles and Impacts Their Phosphoprotein and DNA Content

[ Journal ]

- JOURNAL OF BIOLOGICAL CHEMISTRY

[ Author ]

- Montermini, L Meehan, B Gamier, D Lee, WJ Lee, TH Guha, A Al-Nedawi, K Rake, J

[ Year ]

- 2015

[ Volume ]

- 290

[ Pages ]

- 24534-24546

[ Abstract ]

- Cancer cells emit extracellular vesicles (EVs) containing unique molecular signatures. Here, we report that the oncogenic EGF receptor (EGER) and its inhibitors reprogram phosphoproteomes and cargo of tumor cell-derived EVs. Thus, phosphorylated EGER (P-EGFR) and several other receptor tyrosine kinases can be detected in 1/Vs purified from plasma of tumorbearing mice and from conditioned media of cultured cancer cells. Treatment of EGER-driven tumor cells with second generation EGER kinase inhibitors (EKIs), including CI-1033 and PE-00299804 but not with anti-EGER antibody (Cetuximab) or etoposide, triggers a burst in emission of exosome-like Ells contaming EGER, P-EGER, and genomic DNA (exo-gDNA). The EV release can be attenuated by treatment with inhibitors of exosome biogenesis (GW4869) and caspase pathways (ZVAD). The content of P-EGFR isoforms (Tyr-845, Tyr-1068, and Tyr1173), ERK, and AKT varies between cells and their corresponding EVs and as a function of EKI treatment, Immunocapture experiments reveal the presence of EC-FR and exo-gDNA within the same EV population following EKI treatment. These findings suggest that targeted agents may induce cancer cells to change the EV emission profiles reflective of drug-related therapeutic stress. We suggest that EV-based assays may serve as companion diagnostics for targeted anticancer agents.

[ URL ]

- http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;UT=WOS:000362218900038