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A grafted peptidomimetic for EGFR heterodimerization inhibition: Implications in NSCLC models
Sitanshu S Singh1, George Mattheolabakis1, Xin Gu2
1School of Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA.
Abstract:
Among the lung cancers, approximately 85% are histologically classified as non-small-cell lung cancer (NSCLC), a leading cause of cancer deaths worldwide. Epidermal growth factor receptors (EGFRs) are known to play a crucial role in lung cancer. HER2 overexpression is detected by immunohistochemistry in 2.4%-38% of NSCLC samples. EGFRs have been targeted with three generations of tyrosine kinase inhibitors (TKIs), and drug resistance has become a major issue; HER2 dimerization with EGFR also plays a major role in the development of resistance to TKI therapy. We have designed grafted peptides to bind to the HER2 extracellular domain (ECD) and inhibit protein-protein interactions of EGFR:HER2 and HER2:HER3. A sunflower trypsin inhibitor (SFTI-1) template was used to graft a peptidomimetic compound. Among several grafted peptides, SFTI-G5 exhibited antiproliferative activity in HER2-positive NSCLC cell lines such as Calu-3 cells with an IC50 value of 0.073 μM. SFTI-G5 was shown to bind to ECD of HER2 and inhibit EGFR:HER2 and HER2:HER3 dimerization and inhibit the phosphorylation of HER2 and downstream signaling proteins. As a proof-of-concept, the in vivo activity of SFTI-G5 was evaluated in two NSCLC mouse models. SFTI-G5 was able to inhibit tumor growth in both models. Furthermore, SFTI-G5 was shown to inhibit EGFR dimerization in tissue samples obtained from in vivo models. These grafted peptides can be used as novel dual inhibitors of EGFR dimerization in NSCLC.
Insights
Researchers developed SFTI-G5, a novel peptide inhibitor targeting HER2 in non-small-cell lung cancer (NSCLC). This peptide effectively inhibits tumor growth and protein dimerization, offering a new therapeutic strategy for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Non-small-cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide, with epidermal growth factor receptors (EGFRs) playing a critical role.
- HER2 overexpression occurs in a significant subset of NSCLC, contributing to tyrosine kinase inhibitor (TKI) resistance through dimerization with EGFR and HER3.
- Existing TKI therapies face challenges with drug resistance, necessitating novel therapeutic approaches targeting key signaling pathways.
Purpose of the Study:
- To design and evaluate novel grafted peptides capable of inhibiting HER2-mediated signaling pathways in NSCLC.
- To investigate the potential of these peptides as dual inhibitors of EGFR dimerization and protein-protein interactions.
- To assess the antiproliferative and anti-tumor efficacy of a lead peptide candidate in preclinical NSCLC models.
Main Methods:
- Grafting of a peptidomimetic compound onto a sunflower trypsin inhibitor (SFTI-1) template to create novel peptide inhibitors.
- In vitro assessment of antiproliferative activity using NSCLC cell lines and determination of IC50 values.
- Biochemical assays to confirm binding to HER2 extracellular domain (ECD) and inhibition of EGFR:HER2 and HER2:HER3 dimerization.
- In vivo evaluation of tumor growth inhibition in NSCLC mouse models and analysis of EGFR dimerization in tissue samples.
Main Results:
- The grafted peptide SFTI-G5 demonstrated significant antiproliferative activity against HER2-positive NSCLC cells (IC50 = 0.073 μM).
- SFTI-G5 effectively binds to HER2 ECD, inhibits EGFR:HER2 and HER2:HER3 dimerization, and reduces phosphorylation of HER2 and downstream signaling proteins.
- In vivo studies confirmed SFTI-G5's ability to inhibit tumor growth in NSCLC mouse models and suppress EGFR dimerization in tumor tissues.
Conclusions:
- Grafted peptides, exemplified by SFTI-G5, represent a promising new class of dual inhibitors targeting EGFR dimerization in NSCLC.
- SFTI-G5 shows potential as a therapeutic agent for HER2-positive NSCLC by disrupting critical oncogenic signaling pathways.
- Further development of these peptides could lead to novel treatment strategies to overcome TKI resistance in lung cancer.
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