dll3

Overview

Delta-like 3 protein (DLL3) is a protein that acts as an inhibitory ligand of NOTCH receptors.^1,2
- The NOTCH pathway has been implicated in regulating neuroendocrine versus epithelial cell fate decisions in the developing lung.³
Outside of the developing embryo, DLL3 has minimal to no surface expression in normal tissue.
During normal development, DLL3 localizes to the Golgi apparatus and cytoplasmic vesicles, where it interacts with unprocessed full-length NOTCH1 and DLL1, preventing their localization to the cell surface.^2,4
- DLL3 is also thought to be a transcriptional target of achaete-scute homolog-1 (ASCL1), a transcription factor critical for normal pulmonary neuroendocrine cell (PNEC) development.²

Deregulated NOTCH signaling has a protumorigenic effect in many malignancies; however in neuroendocrine tumors, NOTCH activation suppresses tumor growth.^2,5

Whole transcriptome sequencing of tumor-initiating cells (TICs) isolated from small-cell lung cancer (SCLC) and large-cell neuroendocrine cancer (LCNEC) patient-derived xenografts showed that DLL3 is expressed in most SCLCs and large-cell neuroendocrine tumors (LCNETs).^2,6
- Membrane protein expression is slight to nonexistent in non-malignant adult tissues and non-neuroendocrine tumor types.²
Surface DLL3 expression was detected in 72% of treatment-naïve SCLC, 65% of LCNEC, and 85% of recurrent and treatment-refractory (R/R) SCLC tumor specimens.²
- No normal lung specimen or NSCLC tumor cells stained positive.²
ASCL1 is also highly expressed in SCLC and LCNEC tumors.²
- ASCL1 and DLL3 overexpression correlate with the tumor-initiating capacity of SCLC tumors.²

Kunnimalaiyaan M, Chen H. Tumor suppressor role of notch-1 signaling in neuroendocrine tumors. The Oncologist. 2007;12:535-542.
Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):1-28.
Morimoto M, Nishinakamura R, Saga Y, Kopan R. Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development. 2012;139:4365-4373.
Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand delta-like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Human Mol Genetics. 2011;20(5):905-916.
Brzozowa-Zasada M, Piecuch A, Michalski M, et al. Notch and its oncogenic activity in human malignancies. Eur Surg. 2017;49(5):199-209.
Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42-51.