Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells

Abstract

Although the molecular therapeutics targeting key biomarkers such as epithelial growth factor receptor (EGFR), PI3K/AKT/mTOR, and vascular endothelial growth factor (VEGF) shows some success in clinical trials, some internally existing challenges in endothelial cancer biology hinder the drug effects. One of the major challenges stems from cancer stem cell-derived drug resistance. CD133 positive cells are well believed as cancer stem cells (CSC) in endometrial cancers and NOTCH pathway plays a critical role in retaining CD133C cells by promoting CSC self-renewal and chemoresistance. Here, we initiated a therapeutic strategy to improve effects of EGFR inhibition by targeting NOTCH pathway of CD133C cells in endometrial cancers. We first detected and purified the CD133C cell fraction in endometrial cancer cell line Ishikawa (IK), and validated activation of NOTCH pathway in the CD133C cells that have higher proliferation rate and lower apoptosis rate, comparing to CD133-cells. Results of nude mouse xenograft experiments further demonstrated CD133C cells retain higher tumorigenesis capacity than CD133-cells, indicating their tumorinitiating property. Last, we applied both NOTCH inhibitor DAPT and EGFR inhibitor AG1478 treatment on endometrial cancer lines IK and HEC-1A and the results suggested improvement effects of the combination therapy compared to the treatments of DAPT or AG1478 alone. These findings indicated targeting NOTCH pathway in CD133C cells, combining with EGFR inhibition, which provides a novel therapeutic strategy for endometrial cancer diseases.

Identification of an autophagy-related gene expression prognostic model in endometrial carcinoma patients

“…The alteration analysis results of the top 15 hub genes in our study were in accordance with these ndings. Shang et.al demonstrated the therapeutic effect of targeting the NOTCH pathway could improve the effects of EGFR inhibition in EC [16]. In addition, these dysregulated genes were also enriched in a series of the cancer process, such as lung cancer, colorectal cancer, and pancreatic cancer, which suggests that the disorder of autophagy-related genes is a common event in various cancer types.…”

Identification of an autophagy-related gene expression prognostic model in endometrial carcinoma patients

“…The alteration analysis results of the top 15 hub genes in our study were in accordance with these findings. Shang et.al demonstrated the therapeutic effect of targeting the NOTCH pathway could improve the effects of EGFR inhibition in EC [16]. In addition, these dysregulated genes were also enriched in a series of the cancer process, such as lung cancer, colorectal cancer, and pancreatic cancer, which suggests that the disorder of autophagy-related genes is a common event in various cancer types.…”

Expression Profiles of the Phosphatase and Tensin Homolog (PTEN), CDH1, and CDH2 Genes, and the Cell Membrane Protein, CD133, in the Ishikawa Human Endometrial Adenocarcinoma Cell Line

“…CD133 is composed of 865 amino acids and is expressed in mesenchymal stem cells, endothelial progenitor cells, and other cells [22,23]. CD133 expression has been identified in several types of tumor stem cells, which have the biological characteristics of a malignant phenotype and invasive ability [24][25][26]. Therefore, CD133 is currently recognized as a cell membrane marker of tumor stem cells.…”