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Published on: December 1, 2016
A low-molecular-weight compound exerts anticancer activity against breast and lung cancers by disrupting EGFR/Eps8
Meifang Li1, Jilong Yang1, Lenghe Zhang1
1Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 GongyeDadaoZhong, Guangzhou, Guangdong, 510282, People's Republic of China.
Background:
Epidermal growth factor receptor (EGFR) and epidermal growth factor receptor pathway substrate 8 (Eps8) have been widely reported to be expressed in various tumors. Eps8 is an important active kinase substrate of EGFR that directly binds to the juxtamembrane (JXM) domain of EGFR to form an EGFR/Eps8 complex. The EGFR/Eps8 complex is involved in regulating cancer progression and might be an ideal target for antitumor therapy. This study focused on the screening of small-molecule inhibitors that target the EGFR/Eps8 complex in breast cancer and non-small cell lung cancer (NSCLC).
Methods:
In silico virtual screening was used to identify small-molecule EGFR/Eps8 complex inhibitors. These compounds were screened for the inhibition of A549 and BT549 cell viability. The direct interaction between EGFR and Eps8 was measured using coimmunoprecipitation (CoIP) and JXM domain replacement assays. The antitumor effects of the inhibitors were analyzed in cancer cells and xenograft models. An acute toxicity study of EE02 was performed in a mouse model. In addition, the effect of the EE02 inhibitor on the protein expression of elements downstream of the EGFR/Eps8 complex was determined by western blotting and protein chip assays.
Results:
In this study of nearly 390,000 compounds screened by virtual database screening, the top 29 compounds were identified as candidate small-molecule EGFR/Eps8 complex inhibitors and evaluated by using cell-based assays. The compound EE02 was identified as the best match to our selection criteria. Further investigation demonstrated that EE02 directly bound to the JXM domain of EGFR and disrupted EGFR/Eps8 complex formation. EE02 selectively suppressed growth and induced apoptosis in EGFR-positive and Eps8-positive breast cancer and NSCLC cells. More importantly, the PI3K/Akt/mTOR and MAPK/Erk pathways downstream of the EGFR/Eps8 complex were suppressed by EE02. In addition, the suppressive effect of EE02 on tumor growth in vivo was comparable to that of erlotinib at the same dose.
Conclusions:
We identified EE02 as an EGFR/Eps8 complex inhibitor that demonstrated promising antitumor effects in breast cancer and NSCLC. Our data suggest that the EGFR/Eps8 complex offers a novel cancer drug target.
Insights
Researchers identified EE02, a novel small-molecule inhibitor targeting the epidermal growth factor receptor (EGFR)/Eps8 complex. This compound shows significant promise in suppressing tumor growth and inducing apoptosis in breast cancer and non-small cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptor (EGFR) and its substrate Eps8 form a complex crucial for cancer progression.
- The EGFR/Eps8 complex is a potential therapeutic target for various cancers.
- This study focused on identifying inhibitors for the EGFR/Eps8 complex in breast cancer and non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To screen for small-molecule inhibitors targeting the EGFR/Eps8 complex.
- To evaluate the efficacy of identified inhibitors in preclinical cancer models.
- To validate the EGFR/Eps8 complex as a novel drug target.
Main Methods:
- In silico virtual screening of approximately 390,000 compounds.
- Cell viability assays using A549 and BT549 cancer cell lines.
- Coimmunoprecipitation (CoIP) and JXM domain replacement assays to confirm direct interaction.
- In vivo studies using xenograft models and acute toxicity assessments in mice.
- Western blotting and protein chip assays to analyze downstream signaling pathways.
Main Results:
- Virtual screening identified 29 candidate inhibitors, with EE02 selected for further study.
- EE02 directly binds to the EGFR juxtamembrane (JXM) domain, disrupting EGFR/Eps8 complex formation.
- EE02 demonstrated selective suppression of growth and induction of apoptosis in EGFR/Eps8-positive breast cancer and NSCLC cells.
- EE02 inhibited downstream signaling pathways, including PI3K/Akt/mTOR and MAPK/Erk.
- In vivo antitumor efficacy of EE02 was comparable to erlotinib.
Conclusions:
- EE02 is a potent inhibitor of the EGFR/Eps8 complex with significant antitumor activity in breast cancer and NSCLC.
- The EGFR/Eps8 complex represents a promising novel therapeutic target for cancer treatment.
- Further development of EE02 or similar inhibitors warrants investigation.
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