Delta-like protein 3 (DLL3) is a protein encoded by the DLL3 gene. It belongs to the delta-like family, which are ligands for the Notch signaling pathway. DLL3 is involved in fundamental biological processes within cells, playing a role in cell differentiation, proliferation, and development.
Understanding DLL3
DLL3 is a single transmembrane protein located on the cell surface. It is characterized by a Delta/Serrate/LAG-2 (DSL) domain, six epidermal growth factor (EGF)-like repeats, and a transmembrane domain. The DSL domain, found at the extracellular N-terminal, is highly conserved within the ligand family and is necessary for binding to the Notch receptor. DLL3 functions as a signaling molecule, facilitating communication between cells.
The human DLL3 gene is located on chromosome 19q13 and has an open reading frame of approximately 1800 base pairs. The resulting human DLL3 protein consists of 619 amino acids. Its presence on the cell surface allows it to interact with neighboring cells, influencing cellular behavior.
How DLL3 Functions in Cells
DLL3 plays a role within the Notch signaling pathway, a highly conserved system that regulates cell fate decisions. As a ligand, DLL3 interacts with Notch receptors on adjacent cells. Unlike other Notch ligands that typically activate the pathway, DLL3 often acts as an inhibitor of Notch signaling.
This inhibitory action influences cell development and differentiation. For instance, in the developing embryo, DLL3 is involved in somitogenesis, the formation of somites, which are precursors to skeletal muscle, vertebrae, and dermis. DLL3 helps regulate the “segmentation clock” that controls the periodic formation of these somites. DLL3 has also been observed to activate other pathways by inhibiting Notch signaling.
DLL3’s Connection to Disease
Aberrant expression of DLL3 has been observed in various cancers. It is particularly overexpressed in small cell lung cancer (SCLC), with approximately 80% of primary and metastatic SCLC patients showing DLL3 expression. This overexpression can contribute to tumor growth and proliferation.
DLL3 is also overexpressed in other tumor types, including certain neuroendocrine tumors, stomach cancer cells, and some types of breast cancer. For example, DLL3 interactions have been linked to the regulation of proliferation and invasion in pituitary adenomas, and to cell proliferation and differentiation in ovarian cancer, as well as growth in melanoma.
Targeting DLL3 in Medicine
The distinct expression pattern of DLL3, particularly its high presence in cancer cells and limited expression in healthy adult tissues, positions it as a promising target for cancer therapies. Several strategies are being explored to specifically target DLL3-expressing cells, offering new avenues for treatment.
One approach involves antibody-drug conjugates (ADCs), which combine an antibody that binds to DLL3 with a potent chemotherapy drug. Rovalpituzumab tesirine is an example of an ADC that was investigated for SCLC, designed to deliver a toxic payload directly to DLL3-expressing tumor cells. More recently, Zai Lab’s ZL-1310, another DLL3-targeting ADC, showed significant efficacy and good safety in a Phase 1 clinical trial for metastatic or extensive-stage SCLC.
Another therapeutic strategy utilizes bispecific antibodies, engineered to bind to both DLL3 on tumor cells and an immune cell marker, such as CD3 on T cells. Tarlatamab, a bispecific protein targeting DLL3 and CD3, received accelerated FDA approval in May 2024 for SCLC. This therapy works by bringing the patient’s own T cells into close proximity with DLL3-expressing tumor cells, activating them to kill cancer cells. Chimeric antigen receptor (CAR) T-cell therapies are also under investigation, where a patient’s T cells are genetically modified to express a receptor that recognizes and binds to DLL3 on tumor cells, leading to targeted destruction of the cancer. These advancements illustrate the transition of DLL3 research from laboratory findings to clinical applications, providing new hope for patients with certain cancers.