Roles of NOTCH1 as a Therapeutic Target and a Biomarker for Lung Cancer: Controversies and Perspectives

Abstract

Lung cancer is one of the most common types of human malignancies and the leading cause of cancer-related death. Patients with surgically resectable early stage lung cancer are more likely curable, but currently only a small population of patients can be diagnosed at such a stage, partly due to our incomplete understanding of the biology of lung cancer and the lack of diagnostic and prognostic biomarkers. Recent studies have shown that NOTCH1 is a critical regulator of human carcinogenesis and has been implicated in multiple steps of cancer development and progression. Herein, we review recent findings about the role of NOTCH1 in lung cancer and discuss its potential usefulness as both a therapeutic target and a biomarker for lung cancer.

Figure 1

Schematic for NOTCH signaling in cancer cells. Upon the binding of NOTCH ligands (JAG1, JAG2, DLL1, DLL3, and DLL4) on adjacent cells, such as stromal cells or other cancer cells, NOTCH (NOTCH1–NOTCH4) on cancer cells can be activated through proteolytic cleavage (by ADAM proteinase and γ-secretase) to release its intracellular domain (NICD), which in turn translocates to the nucleus, where it forms transcription complexes with transcription cofactors (the blue shapes) to regulate cell-context-dependent transcription.

Figure 2

Hypothetical role of NOTCH1 in EMT and metastasis. Elevated NOTCH1 activity in epithelial tumor cells may promote EMT through EMT-regulating pathways and transcription factors, such as SNAIL, SLUG, ZEB1, and SOX9. Tumor cells that have undergone EMT display mesenchymal morphology and acquire enhanced invasiveness and metastatic potential. Inhibition of NOTCH1 by NOTCH inhibitors, including γ-secretase inhibitors and NOTCH1 monoclonal antibodies (mAb), may inhibit or reverse EMT and may be useful for treating metastatic cancers.