Abstract 1782
Background
EpCAM is a type I transmembrane glycoprotein with an extracellular domain (EpEX) and an intracellular domain (EpICD), which have 265 and 26 amino acid residues, respectively. EpCAM is highly expressed in advanced epithelial cancers and tumor-initiating cells, but its role in cancer progression remains to be elucidated.
Methods
To identify cell signaling pathways that are stimulated by EpEX, we used a Human Phospho-RTK Array Kit to screen for phosphorylation of RTKs. Inhibition of EpEX-induced EGFR-PI3K-AKT signaling was analyzed by small molecule inhibitors or shRNA knockdown.
Results
Here, we found that EpEX activated AKT signaling, thereby inducing the phosphorylation and nuclear exclusion of FOXO3a. The EGFR inhibitor, AG1478, and MEK inhibitor, U0126, both decreased the production of EpICD, which was found to be necessary for nuclear accumulation of β-catenin protein and expression of HIF1α target genes in vitro and in mouse xenograft models. We also demonstrated that treatment with an anti-EpCAM neutralizing antibody, EpAb2-6, decreased the ADAM17 and γ-secretase activity, the EpCAM-downstream gene expression, and tumor colony and sphere formation. We also found that EpAb2-6 inhibited EpEX-activated EGFR-PI3K-AKT signaling and induced apoptotic signaling through FOXO3a activation of HTRA2 gene expression. Importantly, we also showed that EpAb2-6 inhibited the nuclear translocation of EpICD and oncogenic signaling through β-catenin. Finally, in both metastatic and orthotopic animal models of colorectal cancer, EpAb2-6 therapy exhibited an antitumor effect and markedly extended the survival time of mice.
Conclusions
Our results demonstrate that EpEX contributes to malignancy by functioning as a growth factor, which activates EpICD-mediated signaling, thereby enhancing colon cancer cell survival. To the best of our knowledge, hEpAb2-6 is the first humanized anti-EpCAM antibody to directly trigger apoptosis in cancer cells. Thus, we provide novel insight into EpEX-EGFR signaling, which can be considered as a promising target for treatment of colon cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Academia Sinica.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2888 - Development and validation a nomogram based on pathological microscopic features to predict survival in nasopharyngeal carcinoma and guide treatment decision
Presenter: Kuiyuan Liu
Session: Poster Display session 3
Resources:
Abstract
3607 - Deep learning in nasopharyngeal carcinoma: a retrospective cohort study of 3D convolutional neural networks on magnetic resonance imaging
Presenter: Meng Yun Qiang
Session: Poster Display session 3
Resources:
Abstract
5848 - Combined androgen blockade in patients with advanced androgen receptor–positive salivary gland carcinoma: Exploratory biomarker analyses
Presenter: Chihiro Fushimi
Session: Poster Display session 3
Resources:
Abstract
4484 - Classification of esthesioneuroblastoma (ENB) based on chromosome (chr) arm gain and loss (CNA) in the setting of a hypomutated genomic landscape
Presenter: Russell Madison
Session: Poster Display session 3
Resources:
Abstract
5753 - Trastuzumab plus docetaxel in patients with advanced HER2–positive salivary duct carcinoma: Exploratory biomarker analyses
Presenter: Hideaki Takahashi
Session: Poster Display session 3
Resources:
Abstract
3373 - Development and characterization of salivary gland cancer organoid cultures
Presenter: Wim Boxtel
Session: Poster Display session 3
Resources:
Abstract
3118 - A parent-of-origin effect of the RB1 mutations in retinoblastoma with low penetrance and variable expressivity
Presenter: Ekaterina Alekseeva
Session: Poster Display session 3
Resources:
Abstract
4512 - The humanistic burden reported by patients diagnosed with Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN) in Europe
Presenter: Prianka Singh
Session: Poster Display session 3
Resources:
Abstract
3961 - Concurrent Chemotherapy and External Radiation Therapy: An Open Label Non-Inferiority Phase III Randomized Controlled Trial of Weekly versus Three Weekly Cisplatin and Radical Radiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: CONCERT trial
Presenter: ATUL SHARMA
Session: Poster Display session 3
Resources:
Abstract
3973 - A randomized phase II study on the OPTimization of IMmunotherapy in squamous carcinoma of the head and neck (SCCHN) – OPTIM (AIO-KHT-0117)
Presenter: Viktor Grünwald
Session: Poster Display session 3
Resources:
Abstract