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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung
Hye-Young Min1, Hye Jeong Yun2, Ji-Sun Lee3
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. snoopy77@snu.ac.kr.
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.
Insights
Src and Insulin-like Growth Factor-1 Receptor (IGF-1R) activation drives non-small cell lung cancer (NSCLC) resistance to IGF-1R inhibitors. Targeting Src alongside IGF-1R inhibitors overcomes this resistance, offering a new therapeutic strategy for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Insulin-like Growth Factor-1 Receptor (IGF-1R) pathway inhibitors were anticipated for clinical benefits in cancer.
- However, IGF-1R tyrosine kinase inhibitors (TKIs) exhibit limited antitumor efficacy, with resistance mechanisms remaining unclear.
Purpose of the Study:
- To investigate the interplay between IGF-1R and Src signaling in non-small cell lung cancer (NSCLC).
- To determine the efficacy of combined IGF-1R and Src inhibition in overcoming TKI resistance in NSCLC.
Main Methods:
- Assessed IGF-1R and Src expression and activation using public datasets, immunohistochemistry, Western blotting, RT-PCR, and kinase assays.
- Evaluated IGF-1R TKI efficacy alone and with Src inhibitors via MTT assays, colony formation assays, flow cytometry, and xenograft models.
Main Results:
- Co-activation of IGF-1R and Src was observed in human NSCLC cell lines and patient tissues, with mutual phosphorylation.
- IGF-1R TKIs induced Src-dependent pathway reactivation or amplified IGF-1R/Src co-activation, depending on Src levels.
- Combined targeting of IGF-1R and Src significantly suppressed NSCLC proliferation and tumor growth in vitro and in vivo.
Conclusions:
- Reciprocal activation between Src and IGF-1R contributes to NSCLC progression and resistance to IGF-1R TKIs.
- Src acts as a critical downstream modulator, mediating cross-talk between membrane receptors and conferring resistance.
- Targeting Src represents a clinically viable strategy to enhance the efficacy of IGF-1R TKIs in NSCLC treatment.
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