作者: Hye-Young Min , Hye Jeong Yun , Ji-Sun Lee , Hyo-Jong Lee , Jaebeom Cho
DOI: 10.1186/S12943-015-0392-3
关键词: Autophosphorylation 、 Linsitinib 、 Proto-oncogene tyrosine-protein kinase Src 、 Biology 、 Cancer research 、 Cell surface receptor 、 Growth factor receptor inhibitor 、 Tyrosine kinase 、 Signal transduction 、 Growth factor receptor
摘要: Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and mechanisms conveying resistance these agents remain elusive. The expression activation of Src assessed via analysis a publicly available dataset, as well immunohistochemistry, Western blotting, RT-PCR, vitro assays. efficacy TKIs alone or combination with was analyzed using MTT assays, colony formation flow cytometric analysis, xenograft tumor models. co-activation observed multiple human NSCLC cell lines tissue microarray (n = 353). proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing cells, linsitinib treatment initially inactivated but led Src-dependent reactivation downstream effectors. low-pSrc-expressing decreased turnover proteins, ultimately amplifying reciprocal Src. Co-targeting significantly suppressed proliferation both cells vivo patient-derived tissues vivo. Reciprocal between occurs NSCLC. causes TKI by acting key modulator cross-talk membrane receptors. Targeting is clinically applicable strategy overcome TKIs.