A brief overview of clinical significance of novel Notch2 regulators

Figures & data

Figure 1. Structure of the Notch2 receptor. NECD – Notch extracellular domain, NRR – negative regulatory region, TM – transmembrane domain, NICD – Notch intracellular domain, EGF – epidermal growth factor, LNR – cysteine-rich Lin repeats, HD – heterodimerization domain, RAM – RAM domain, ANK – ankyrin repeats, NCR – cysteine response region, TAD – transactivation domain, PEST – transactivation domain rich in proline (P), glutamine (E), serine (S), and threonine (T) residues.

Table 1. The list of notch2 regulators and clinical implications.

Notch2 regulators	Disease	Mechanism of regulaton	Source
Gliotoxin	Melanoma	Inhibitor	Hubmann R. et.al. Pharmacol.^Citation17
	Chronic lymphocytic leukemia (CLL) cells	Inhibitor	Hubmann R. et.al. Br J Haematol.^Citation20
Tarextumab (OMP‐59R5)	Metastatic pancreatic cancer	Inhibitor	Hu Zi. et.al. Cancer Med.
	Solid tumors	Inhibitor	Smith DC. et.al. Invest New Drugs.^Citation27
	Small cell lung cancer	Inhibitor	Lu H. et.al. Adv Clin Exp Med.^Citation21
		Inhibitor	Hu S. et.al. Sci Transl Med.
		Inhibitor	Yen WC. Et.al. Clin Cancer Res.^Citation22
Minar1	Breast cancer	Inhibitor	Ho RX. et al. J Mol Cell Biol.^Citation28
N-acetylcysteine (NAC)	Glioblastoma	Inhibitor	Jie Deng. et.al. J Exp Clin Cancer Res.^Citation29
Long Non-coding RNA (lncRNA) MIR22HG	Gastric cancer	Inhibitor	Zhang X. et.al. Mol Cancer.^Citation33 Li H. etl.al. Med Sci Monit.^Citation34

Hubmann R, Sieghart W, Schnabl S, Araghi M, Hilgarth M, Reiter M, Demirtas D, Valent P, Zielinski C, Jäger U, et al. Gliotoxin targets nuclear NOTCH2 in human solid tumor derived cell lines in vitro and inhibits melanoma growth in xenograft mouse model. Front Pharmacol. 2017 Jul 7;8:319. doi:10.3389/fphar.2017.00319.

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Hubmann R, Hilgarth M, Schnabl S, Ponath E, Reiter M, Demirtas D, Sieghart W, Valent P, Zielinski C, Jäger U, et al. Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. Br J Haematol. 2013 Mar;160(5):618–629. doi:10.1111/bjh.12183.

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Smith DC, Chugh R, Patnaik A, Papadopoulos KP, Wang M, Kapoun AM, Xu L, Dupont J, Stagg RJ, Tolcher, et al. A phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors. A Invest New Drugs. 2019 Aug;37(4):722–730. doi:10.1007/s10637-018-0714-6.

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Lu H, Jiang Z. Advances in antibody therapeutics targeting small-cell lung cancer. Adv Clin Exp Med. 2018 Sep;27(9):1317–1323. doi:10.17219/acem/70159.

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Yen WC, Fischer MM, Axelrod F, Bond C, Cain J, Cancilla B, Henner WR, Meisner R, Sato A, Shah J, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 2015 May 1;21(9):2084–2095. doi:10.1158/1078-0432.CCR-14-2808.

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Ho RX, Meyer RD, Chandler KB, Ersoy E, Park M, Bondzie PA, Rahimi N, Xu H, Costello CE, Rahimi N. MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth. J Mol Cell Biol. 2018 Jun 1;10(3):195–204. doi:10.1093/jmcb/mjy002.

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Deng J, Liu A-D, Hou G-Q, Zhang X, Ren K, Chen X-Z, Li SSC, Wu Y-S, Cao X. N-acetylcysteine decreases malignant characteristics of glioblastoma cells by inhibiting Notch2 signaling. J Exp Clin Cancer Res. 2019;38:2. doi:10.1186/s13046-018-1016-8.

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Zhang X, Xie K, Zhou H, Wu Y, Li C, Liu Y, Liu Z, Xu Q, Liu S, Xiao D, et al. Role of non-coding RNAs and RNA modifiers in cancer therapy resistance. Mol Cancer. 2020 Mar 2;19(1):47. doi:10.1186/s12943-020-01171-z.

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Li H, Wang Y. Long noncoding RNA (lncRNA) MIR22HG suppresses gastric cancer progression through attenuating NOTCH2 signaling. Med Sci Monit. 2019 Jan 23;25:656–665. doi:10.12659/MSM.912813.

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