Prosecretin (EREG) is a ligand for epidermal growth factor receptor /EGFR and ERBB4. It promotes tyrosine phosphorylation of EGFR and ERBB4. It participates in inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and stimulating cell proliferation.
Expression distribution of EREG
EREG is mainly expressed in lymphoid and bone marrow tissues. EREG is mainly expressed in monocytes, and is also expressed in small amounts in macrophages, Hofbauer cells, Kupffer cells, dendritic cells, and Langerhans cells.
(Data source: Uniprot)
Structure and receptors of EREG
EREG is a single-pass type I membrane protein composed of 169 amino acids, with a signal peptide, an N-terminal extracellular region, a transmembrane region, and a C-terminal cytoplasmic region. The extracellular region contains an epidermal growth factor-like domain .
EREG is initially synthesized as a precursor protein, proepiregulin, with a molecular weight of approximately 19 kDa (unglycosylated). Glycosylation then results in a transmembrane protein of approximately 30 kDa. Under the action of integrins and metalloproteinases, proepiregulin is cleaved to release the mature EREG polypeptide, which consists of approximately 46-50 amino acids.
( Data source: uniprot )
EREG signal transduction and its role in the tumor microenvironment
Soluble EREG binds to EGFR (ERBB1) and ERBB4, inducing receptor homo- or heterodimerization. By binding to EGFR (ERBB1/HER1) and ErbB4 (HER4), EREG activates downstream signaling pathways, including the RAS/RAF/MEK/ERK pathway , the PI3K/AKT/mTOR pathway , and the JAK/STAT pathway . These pathways act on tumor cells and other cells within the TME (such as fibroblasts and macrophages) through autocrine, paracrine, or juxtacrine pathways.
(Data source: Wang C. Oncogene. 2022)
Promote tumor occurrence and progression
Autocrine and paracrine EREG may primarily activate pathways downstream of EGFR that contribute to tumorigenesis in the TME of various cancers. In colitis-associated cancers, stromal-derived EREG promotes intestinal epithelial cell proliferation through the ERK pathway.
EREG mediates tumor metastasis
EREG induces the transformation of normal fibroblasts into CAFs through JAK2/STAT3 and IL-6 signaling, thereby promoting the EMT of tumor cells. EREG expression may be induced in colon CSCs and is associated with drug resistance. In breast cancer, EREG is one of the "lung metastasis signature" (LMS) genes, synergizing with MMP1/2 and COX2 to promote lung metastasis. In models of head and neck cancer and salivary gland cancer, EREG enhances cell migration through the EGFR/ERK/AKT pathway.
Promotes cancer stem cell (CSC) properties
Increased EREG expression in CRC cells is associated with cancer stem cell (CSC) characteristics and plays a key role in metastasis during tumor progression. In colon cancer, EREG is expressed in both LGR5-positive and drug-resistant LGR5-negative stem cells, suggesting a role in stem cell maintenance and drug resistance transitions. In gliomas, EREG expression is positively correlated with the mRNA-based stemness index, suggesting that it promotes cancer stem cell characteristics.
Mediated drug resistance
EGFR-TKI resistance: In NSCLC, EREG secreted by tumor-associated macrophages (TAMs) induces resistance to EGFR-TKIs (such as erlotinib) through the EGFR/ERBB2/AKT pathway. In colorectal cancer, EREG mediates 5-FU resistance through the miR-215-5p/TYMS axis. In breast cancer, EREG induces tamoxifen resistance by activating EGFR signaling and promoting the Warburg effect (aerobic glycolysis).
( Data source: Cheng WL, et al. Int J Mol Sci. 2021)
EREG -targeted therapy
LY-3848575 is a monoclonal antibody targeting EREG developed by Eli Lilly and Company. Eli Lilly is conducting a Phase 2 study entitled "A Phase 2, randomized, double-blind, placebo-controlled, dose-finding study evaluating LY3848575 in chronic neuropathic pain associated with distal sensory polyneuropathy." The study aims to evaluate the safety and efficacy of LY3848575 compared with placebo in treating nerve pain that starts in the feet and progresses up the legs.
Fepixnebart ( LY3016859 ), a bispecific antibody targeting TGFA and EREG, is being developed by Eli Lilly and Company. An ongoing study (NCT04529096) is testing the safety and efficacy of LY3016859 in the treatment of osteoarthritis pain. This trial is part of the H0P-MC-CPMP ( NCT05986292 ) master program for chronic pain , which aims to accelerate the development of new treatments for chronic pain.
