Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer

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: AutophosphorylationLinsitinibProto-oncogene tyrosine-protein kinase SrcBiologyCancer researchCell surface receptorGrowth factor receptor inhibitorTyrosine kinaseSignal transductionGrowth 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.

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