Precision medicine for human cancers with Notch signaling dysregulation (Review)

Abstract

NOTcH1, NOTcH2, NOTcH3 and NOTcH4 are transmembrane receptors that transduce juxtacrine signals of the delta-like canonical Notch ligand (dLL)1, dLL3, dLL4, jagged canonical Notch ligand (JAG)1 and JAG2. canonical Notch signaling activates the transcription of BMI1 proto-oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context-dependent manner, while non-canonical Notch signaling activates NF-κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non-small-cell lung cancer and hematological malignancies, such as T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, Notch signaling is inactivated in small-cell lung cancer and squamous cell carcinomas. Loss-of-function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain-of-function NOTCH1 mutations are late events during T-cell leukemogenesis and B-cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor-suppressive effects in a cancer stage-or (sub)type-dependent manner. Small-molecule γ-secretase inhibitors (AL101, MRK-560, nirogacestat and others) and antibody-based biologics targeting Notch ligands or receptors [ABT-165, AMG 119, rovalpituzumab tesirine (Rova-T) and others] have been developed as investigational drugs. The dLL3-targeting antibody-drug conjugate (Adc) Rova-T, and dLL3-targeting chimeric antigen receptor-modified T cells (CAR-Ts), AMG 119, are promising anti-cancer therapeutics, as are other Adcs or cARTs targeting tumor necrosis factor receptor superfamily member 17, cd19, cd22, cd30, cd79B, cd205, claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor-type tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor receptor, NEcTIN4, inactive tyrosine-protein kinase 7, inactive tyrosine-protein kinase transmembrane receptor ROR1 and tumor-associated calcium signal transducer 2. Adcs and cARTs could alter the therapeutic framework for refractory cancers, especially diffuse-type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova-T for patients with small-cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch-related knowledge-base and optimize Notch-targeted therapy for patients with cancer.

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…Since cytotoxic cancer therapeutics are designed to kill actively dividing cells, this can lead to selection of nondividing stem cells that still have the capacity to migrate and establish tumors at distant sites. Several studies have implicated Rac and Cdc42 signaling in stem cell maintenance through activation of Wnt, Notch, and YAP signaling in breast cancer, NSCLC, and lymphomas (De et al, 2017;Hicks-Berthet and Varelas, 2017;Lai et al, 2017;Olabi et al, 2018;Katoh and Katoh, 2020). Therefore, as has been shown by us using mammosphere assays, Rac/Cdc42 inhibition can reduce stem cell-like growth in breast cancer (Humphries-Bickley et al, 2017).…”

Synergistic antitumor activity of a DLL4/VEGF bispecific therapeutic antibody in combination with irinotecan in gastric cancer

“…Therefore, regulation of CSCs through the development of novel agents may improve the treatment and survival of GC patients. Notch signaling triggered by the interaction of DLL4 plays a crucial role in GC stem cell pathology ( 28 ). Here, we demonstrate DLL4 inhibition using both anti-DLL4 and ABL001 significantly reduced the stem-like phenotype in GC and anti-mouse mABL001 administration significantly reduced the tumor burden in both xenograft and orthotopic GC-bearing mice.…”

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

“…This signaling is also involved in the regulation of stem cell differentiation and maintenance [ 182 , 183 ]. Notch signaling activation occurs via an interaction between four Notch receptors (Notch 1–4) and five canonical ligands (Jag1, Jag2, Dll1, Dll3, and Dll4) [ 184 , 185 ]. It has been shown that Notch 1 and 2 share a similar basic structure and are ubiquitously expressed in a wide variety of tissues and cells types at varying levels [ 186 , 187 ].…”