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Updated: Jul 6, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Structure-guided discovery and evaluation of an EGFR L858R-targeting peptide with antiproliferative activity against
Yinxing Zhu1, Hanying Wu2, Xiaohao Liu2
1Department of Traditional Chinese Medicine, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou, China.
Abstract:
EGFR L858R is an activating mutation associated with aberrant EGFR signalling, and molecules capable of recognising this mutant remain of research interest. In this study, a virtual peptide library containing 59 319 heptapeptides was screened against the EGFR L858R crystal structure, leading to the identification of four peptides with favourable predicted binding ability. Among them, Peptide-1 showed the strongest binding affinity in MST assays (Kd = 0.35 ± 0.02 μM), with higher affinity than the reference peptide DTP-1. Integrated structural and dynamic analyses showed that Peptide-1 could form a relatively stable binding conformation with EGFR L858R. Peptide-1 reduced the viability of SKOV3, OVCAR3, and CaOV3 cells, showed weaker effects on IOSE-80 cells, and its activity was markedly attenuated after EGFR-targeting shRNA transduction. In addition, Peptide-1 decreased Cyclin D1 mRNA expression and increased Caspase-3 mRNA expression. These findings indicate that Peptide-1 can be further investigated as an EGFR L858R-targeting peptide.
Insights
Researchers identified Peptide-1, a novel molecule that effectively targets the EGFR L858R mutation. This peptide demonstrates significant potential for developing new therapies against EGFR-mutated cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Activating mutations in Epidermal Growth Factor Receptor (EGFR), such as L858R, drive aberrant signaling in various cancers.
- Developing specific inhibitors for mutant EGFR remains a critical area of cancer research.
Purpose of the Study:
- To identify novel peptides targeting the EGFR L858R mutation.
- To characterize the binding affinity, structural stability, and functional effects of identified peptides.
Main Methods:
- Virtual screening of a large heptapeptide library against the EGFR L858R crystal structure.
- Experimental validation using Micro Scale Thermophoresis (MST) assays to determine binding affinity.
- Cell viability assays, gene expression analysis (mRNA levels of Cyclin D1 and Caspase-3), and shRNA-mediated gene knockdown.
Main Results:
- Four peptides with favorable predicted binding to EGFR L858R were identified; Peptide-1 exhibited the strongest binding affinity (Kd = 0.35 ± 0.02 μM).
- Peptide-1 demonstrated stable binding conformation with EGFR L858R and reduced the viability of EGFR-mutated cancer cell lines (SKOV3, OVCAR3, CaOV3).
- Peptide-1 modulated downstream signaling by decreasing Cyclin D1 and increasing Caspase-3 mRNA expression, with activity dependent on EGFR expression.
Conclusions:
- Peptide-1 is a promising candidate for targeting EGFR L858R mutations.
- Further investigation of Peptide-1 as a therapeutic agent for EGFR-mutated cancers is warranted.
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