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

@entity1 @entity7242 @entity31057 @entity5 @entity98 @entity2856 @entity4149
BACKGROUND: Therapeutic interventions in the insulin-like growth factor receptor ( @entity2856 ) pathway were expected to provide clinical benefits; however, @entity2856 @entity4149 kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive. METHODS: The expression and activation of the @entity2856 and @entity7242 were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of @entity2856 TKIs alone or in combination with @entity7242 inhibitors was analyzed using @entity98 assays, colony formation assays, flow cytometric analysis, and xenograft @entity5 models. RESULTS: The co-activation of @entity2856 and @entity7242 was observed in multiple @entity1 NSCLC cell lines as well as in a tissue microarray (n   =   353). The @entity2856 and @entity7242 proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, @entity31057 treatment initially inactivated the @entity2856 pathway but led a @entity7242 -dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, @entity31057 treatment decreased the turnover of the @entity2856 and @entity7242 proteins, ultimately amplifying the reciprocal co-activation of @entity2856 and @entity7242 . Co-targeting @entity2856 and @entity7242 significantly suppressed the proliferation and @entity5 growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of @entity1 -derived tissues in vivo. CONCLUSIONS: Reciprocal activation between @entity7242 and @entity2856 occurs in NSCLC. @entity7242 causes @entity2856 TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting @entity7242 is a clinically applicable strategy to overcome resistance to @entity2856 TKIs.
