Cargando…
c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma
c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Sr...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339729/ https://www.ncbi.nlm.nih.gov/pubmed/34367939 http://dx.doi.org/10.3389/fonc.2021.602900 |
_version_ | 1783733650929483776 |
---|---|
author | Min, Weili He, Chenyang Zhang, Shuqun Zhao, Yang |
author_facet | Min, Weili He, Chenyang Zhang, Shuqun Zhao, Yang |
author_sort | Min, Weili |
collection | PubMed |
description | c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with “PDEP” motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs. |
format | Online Article Text |
id | pubmed-8339729 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83397292021-08-06 c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma Min, Weili He, Chenyang Zhang, Shuqun Zhao, Yang Front Oncol Oncology c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with “PDEP” motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs. Frontiers Media S.A. 2021-07-22 /pmc/articles/PMC8339729/ /pubmed/34367939 http://dx.doi.org/10.3389/fonc.2021.602900 Text en Copyright © 2021 Min, He, Zhang and Zhao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Min, Weili He, Chenyang Zhang, Shuqun Zhao, Yang c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma |
title | c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma |
title_full | c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma |
title_fullStr | c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma |
title_full_unstemmed | c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma |
title_short | c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma |
title_sort | c-src increases the sensitivity to tkis in the egfr-mutant lung adenocarcinoma |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339729/ https://www.ncbi.nlm.nih.gov/pubmed/34367939 http://dx.doi.org/10.3389/fonc.2021.602900 |
work_keys_str_mv | AT minweili csrcincreasesthesensitivitytotkisintheegfrmutantlungadenocarcinoma AT hechenyang csrcincreasesthesensitivitytotkisintheegfrmutantlungadenocarcinoma AT zhangshuqun csrcincreasesthesensitivitytotkisintheegfrmutantlungadenocarcinoma AT zhaoyang csrcincreasesthesensitivitytotkisintheegfrmutantlungadenocarcinoma |