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.