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

Implications in cancer

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

Small Cell Lung Cancer (SCLC)/Neuroendocrine Tumors (NETs)

  • 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
  1. Kunnimalaiyaan M, Chen H. Tumor suppressor role of notch-1 signaling in neuroendocrine tumors. The Oncologist. 2007;12:535-542.
  2. 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.
  3. 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.
  4. 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.
  5. Brzozowa-Zasada M, Piecuch A, Michalski M, et al. Notch and its oncogenic activity in human malignancies. Eur Surg. 2017;49(5):199-209.
  6. 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.

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