[ 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
[ 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