Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer
|dc.contributor.author||Yun, Hye Jeong||-|
|dc.contributor.author||Lee, J. Jack||-|
|dc.contributor.author||Wistuba, Ignacio I.||-|
|dc.identifier.citation||Molecular Cancer, 14(1):113||ko_KR|
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 the mechanisms conveying resistance to these agents remain elusive.
The expression and activation of the IGF-1R and Src 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 IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models.
The co-activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo.
Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs.
|dc.subject||Insulin-like growth factor receptor||ko_KR|
|dc.title||Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer||ko_KR|
|dc.rights.holder||Min et al.; licensee BioMed Central.||-|
- Appears in Collections:
- College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
- Files in This Item:
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.