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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Hye-Young Min, Hye Jeong Yun, Ji-Sun Lee, Hyo-Jong Lee, Jaebeom Cho, Hyun-Ji Jang, Shin-Hyung Park, Diane Liu, Seung-Hyun Oh, J Jack Lee, Ignacio I Wistuba, Ho-Young Lee
• Journal: Molecular cancer (Mol Cancer) Vol. 14 Pg. 113 (Jun 04 2015) ISSN: 1476-4598 [Electronic] England
• PMID: 26041671 (Publication Type: Journal Article)

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• Imidazoles
• Protein Kinase Inhibitors
• Pyrazines
• Receptor, IGF Type 1
• src-Family Kinases

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Imidazoles (pharmacology)
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Models, Biological
• Molecular Targeted Therapy
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Stability (drug effects)
• Pyrazines (pharmacology)
• Receptor, IGF Type 1 (metabolism)
• Signal Transduction (drug effects)
• src-Family Kinases (metabolism)