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Application of epidermal growth factor receptor kinase substrate 8-type protein 3 to enhancement of curative effect of multi-target kinase inhibitor

A technology of epidermal growth factor and receptor kinase, which is applied in the medical field and can solve problems such as limited use and prolonged median survival time

Active Publication Date: 2020-09-04
CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the median survival associated with this treatment is only a few months, and is often due to tyrosine kinase mutations with subsequent multidrug resistance
Side effects caused by high doses of sorafenib also limit the use of the drug

Method used

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  • Application of epidermal growth factor receptor kinase substrate 8-type protein 3 to enhancement of curative effect of multi-target kinase inhibitor
  • Application of epidermal growth factor receptor kinase substrate 8-type protein 3 to enhancement of curative effect of multi-target kinase inhibitor
  • Application of epidermal growth factor receptor kinase substrate 8-type protein 3 to enhancement of curative effect of multi-target kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1. EPS8L3 is up-regulated in HCC patients and is associated with poor prognosis

[0093] The TCGA database (The Cancer Genome Atlas, TCGA) provides valuable and rich genome and transcriptome analysis data based on human tumors (Tomczak et al., 2015). In order to determine the genes related to HCC, the inventors used the hepatocellular carcinoma RNA data information in the TCGA database to compare the gene expression of the tumor and the corresponding normal tissues adjacent to the tumor.

[0094] Based on transcriptomics, analyze the biological coefficients of the respective variables ( Figure 1A ), suggesting the role of oncogenes in the process of tumor transformation. Subsequently, the inventors compared gene expression in tumor tissues and normal tissues, assuming that the up-regulated genes in HCC specimens are related to tumor formation. EPS8L3 is one of the most up-regulated genes, and the expression in tumor tissues is 60% of that in normal tissues. Times ( ...

Embodiment 2

[0096] Example 2. EPS8L3 affects signal pathways related to cell proliferation

[0097] In order to better understand the molecular mechanism of EPS8L3, the present inventors used shRNA to knock down EPS8L3 in liver cancer cells for unbiased transcriptomics analysis. The RNA expression of EPS8L3 in four liver cancer cells was detected by qRT-PCR ( Figure 2A ) Found that the ΔCt values ​​of BEL-7404 (from liver cancer tissue from Chinese population) and HepG2 (from liver cancer tissue from white men) were lower than BEL-7402 and SMMC-7721 (from liver cancer tissue from Chinese population), namely BEL-7404 and HepG2 EPS8L3RNA The expression level is high.

[0098] After knocking down EPS8L3 in BEL-7404 and HepG2 cells with shRNA, the RNA and protein expression of EPS8L3 were reduced ( Figure 2B to Figure 2D ).

[0099] Microarray sequencing was performed on BEL-7404 and HepG2 cells with high EPS8L3 expression. PCA dot graph is visible ( Figure 2E ), knocking down EPS8L3 has an eff...

Embodiment 3

[0100] Example 3. Inhibiting cell proliferation and mediating cell apoptosis by inhibiting EPS8L3

[0101] Celigo cell imaging and MTT method were used to detect the proliferation ability of BEL-7404 and HepG2 cells (high expression of EPS8L3) after EPS8L3 knockdown. The results showed that the proliferation of HCC cells was significantly inhibited after EPS8L3 knockdown ( Figure 3A to Figure 3D , Figure 3E , Figure 3F ). The proportion of liver cancer cells with different cell cycles after EPS8L3 knockdown was sorted by flow cytometry analysis. In the two cell lines, knocking down EPS8L3 significantly increased the proportion of cells in G1 phase and decreased the proportion of cells in S phase ( Figure 3G to Figure 3I ). Since the cells in the G1 phase do not directly enter cell division, they may also enter the quiescent G0 phase. The increase of cells in the G1 phase is not conducive to cell proliferation. The S-phase DNA replication is fully prepared for the upcoming ce...

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Abstract

The invention relates to an application of epidermal growth factor receptor kinase substrate 8-type protein 3 to enhancement of the curative effect of a multi-target kinase inhibitor. The epidermal growth factor receptor kinase substrate 8-type protein 3 (EPS8L3) is a novel oncogene for HCC. In-vivo and in-vitro experiments prove that the growth potential of HCC tumor cells can be reduced by knocking down the EPS8L3. In addition, cells knocked down in EPS8L3 are more sensitive to treatment of sorafenib. The technical scheme provided by the invention not only provides important factors for HCCprogress, but also provides a potential treatment target for late HCC treatment.

Description

Technical field [0001] The invention relates to the medical field. Specifically, it relates to the synergistic effect of epidermal growth factor receptor kinase substrate class 8 protein 3 and sorafenib. Background technique [0002] Liver cancer is a common tumor. There are 780,000 newly diagnosed liver cancer patients worldwide each year (Ferlay et al., 2015), of which approximately three-quarters are primary hepatocellular carcinoma (HCC) (Siegel et al. , 2018). Hepatitis virus, alcoholism, obesity, diabetes, and smoking are all closely related to the occurrence and development of HCC (Yang and Roberts 2010). Although some early HCC can be cured by surgical resection or liver transplantation, advanced HCC still lacks better treatments. In fact, sorafenib, regorafenib and other related multi-target kinase inhibitors are the only therapeutic drugs for patients with advanced HCC. In addition, although more than a dozen drugs have undergone clinical trials for the treatment of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P35/00C12Q1/6886
CPCA61K45/00A61P35/00C12Q1/6886C12Q2600/158C12Q2600/118
Inventor 陈波李晔雄潘艳许新刘建香
Owner CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI
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