Notch Signalling as a Therapeutic Target in Cancer

Ioana Martinas, Edward Thomas Parkin


Notch signalling is a conserved developmental pathway involved, inter alia, in cell-fate decision, morphogenesis and tissue patterning. Extensive research has linked this pathways with a variety of malignancies, cancer stem cell renewal, induction of epithelial-to-mesenchymal transition and tumor angiogenesis. These data indicate that Notch can act as both a tumor suppressor and an oncoprotein, depending upon cellular context and identify it as a potential therapeutic target in cancer treatment. This review discusses the implications of Notch in a number of hematologic and solid malignancies and some of the currently available inhibitors developed against this pathway as potential cancer therapeutics. 


Notch, Cancer, Receptor, Ligand, Signalling


Dexter J. The analysis of a case of continuous variation in Drosophila by a study of its linkage relations. The American Naturalist. 1914;48(576):712.

Morgan TH. The theory of the gene. The American Naturalist. 1917;51(609):513-44.

Kidd S, Kelley MR, Young MW. Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol Cell Biol. 1986;6(9):3094-108.

Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell. 1985;43(3Pt2):567-81.

D'Souza B, Meloty-Kapella L, Weinmaster G. Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010;92:73-129.

Luo B, Aster JC, Hasserjian RP, et al. Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol Cell Biol. 1997;17(10):6057-67.

Artavanis-Tsakonas S, Rand M, Lake R. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770-6.

Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol. 2007;194(3):459-74.

Muskavitch MA. Delta-notch signaling and Drosophila cell fate choice. Dev Biol. 1994;166(2):415-30.

Hansson EM, Lendahl U, Chapman G. Notch signaling in development and disease. Semin Cancer Biol. 2004;14(5):320-8.

Ntziachristos P, Lim JS, Sage J, et al. From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell. 2014;25(3):318-34.

Logeat F, Bessia C, Brou C et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA. 1998;95(14):8108-12.

Previs RA, Coleman RL, Harris AL, et al. Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res. 2015;21(5):955-61.

Rebay I, Fleming RJ, Fehon RG, et al. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell. 1991;67(4):687-99.

Blaumueller CM, Qi H, Zagouras P, et al. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell. 1997;90(2):281-91.

South AP, Cho RJ, Aster JC. The double-edged sword of Notch signaling in cancer. Semin Cell Dev Biol. 2012.

Malecki MJ, Sanchez-Irizarry C, Mitchell JL, et al. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol. 2006;26(12):4642-51.

Okajima T, Irvine KD. Regulation of notch signaling by o-linked fucose. Cell. 2002;111(6):893-904.

Shi S, Stanley P. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc Natl Acad Sci USA. 2003;100(9):5234-9.

Gordon WR, Vardar-Ulu D, Histen G, et al. Structural basis for autoinhibition of Notch. Nat Struct Mol Biol. 2007;14(4):295-300.

Li K, Li Y, Wu W et al. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem. 2008;283(12):8046-54.

Brou C, Logeat F, Gupta N et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000;5(2):207-16.

Mumm JS, Schroeter EH, Saxena MT, et al. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell. 2000;5(2):197-206.

De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398(6727):518-22.

Six E, Ndiaye D, Laabi Y, et al. The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc Natl Acad Sci USA. 2003;100(13):7638-43.

Al-Hussaini H, Subramanyam D, Reedijk M, et al. Notch signaling pathway as a therapeutic target in breast cancer. Mol Cancer Ther. 2011;10(1):9-15.

Shah S, Lee SF, Tabuchi K, et al. Nicastrin functions as a gamma-secretase-substrate receptor. Cell. 2005;122(3):435-47.

Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998;393(6683):382-6.

Kao HY, Ordentlich P, Koyano-Nakagawa N, et al. A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. 1998;12(15):2269-77.

Nam Y, Sliz P, Song L, et al. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell. 2006;124(5):973-83.

Petcherski AG, Kimble J. Mastermind is a putative activator for Notch. Curr Biol. 2000;10(13):R471-3.

Weng AP, Nam Y, Wolfe MS et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. 2003;23(2):655-64.

Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. 2009;66(10):1631-46.

Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 2013;34(7):1420-30.

Kageyama R, Ohtsuka T, Kobayashi T. The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development. 2007;134(7):1243-51.

Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003;194(3):237-55.

Ronchini C, Capobianco AJ. Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol. 2001;21(17):5925-34.

Zhang P, Yang Y, Nolo R, et al. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness. Oncogene. 2010;29(20):2916-26.

Hoffman B, Liebermann DA. Apoptotic signaling by c-MYC. Oncogene. 2008;27(50):6462-72.

Cmielova J, Rezacova M. p21Cip1/Waf1 protein and its function based on a subcellular localization. J Cell Biochem. 2011;112(12):3502-6.

Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006;25(51):6680-4.

Landolfo S, Gariglio M, Gribaudo G, et al. The Ifi 200 genes: an emerging family of IFN-inducible genes. Biochimie. 1998;80(8-9):721-8.

Qi B, Newcomer RG, Sang QX. ADAM19/adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases. Curr Pharm Des. 2009;15(20):2336-48.

Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22(53):8590-607.

P.Z. M. Hox genes in development; the Hox code. Nature Education. 2008;1(1):2.

Medici D, Hay ED, Olsen BR. Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell. 2008;19(11):4875-87.

Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther. 2006;5(5):1087-98.

Lamar E, Deblandre G, Wettstein D, et al. Nrarp is a novel intracellular component of the Notch signaling pathway. Genes Dev. 2001;15(15):1885-99.

Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity. 2011;35(3):337-48.

Espinoza I, Miele L. Notch inhibitors for cancer treatment. Pharmacol Ther. 2013;139(2):95-110.

Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev. 2004;14(1):48-54.

Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-89.

Le Borgne R. Regulation of Notch signalling by endocytosis and endosomal sorting. Current Opinion in Cell Biology. 2006;18(2):213-22.

Andersen P, Uosaki H, Shenje LT, et al. Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol. 2012;22(5):257-65.

Lindsell CE, Shawber CJ, Boulter J, et al. Jagged: a mammalian ligand that activates Notch1. Cell. 1995;80(6):909-17.

Ladi E, Nichols JT, Ge W, et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol. 2005;170(6):983-92.

Chitnis A. Why is delta endocytosis required for effective activation of notch? Dev Dyn. 2006;235(4):886-94.

Hamel S, Fantini J, Schweisguth F. Notch ligand activity is modulated by glycosphingolipid membrane composition in Drosophila melanogaster. J Cell Biol. 2010;188(4):581-94.

Varnum-Finney B, Wu L, Yu M, et al. Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. J Cell Sci. 2000;113 Pt 23:4313-8.

Bland CE, Kimberly P, Rand MD. Notch-induced proteolysis and nuclear localization of the Delta ligand. J Biol Chem. 2003;278(16):13607-10.

Dyczynska E, Sun D, Yi H, et al. Proteolytic processing of delta-like 1 by ADAM proteases. J Biol Chem. 2007;282(1):436-44.

LaVoie MJ, Selkoe DJ. The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem. 2003;278(36):34427-37.

Parr-Sturgess CA, Rushton DJ, Parkin ET. Ectodomain shedding of the Notch ligand Jagged1 is mediated by ADAM17, but is not a lipid-raft-associated event. Biochem J. 2010;432(2):283-94.

Koo BK, Yoon MJ, Yoon KJ, et al. An obligatory role of mind bomb-1 in notch signaling of mammalian development. PLoS One. 2007;2(11):e1221.

Song R, Koo BK, Yoon KJ, et al. Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1. J Biol Chem. 2006;281(47):36391-400.

Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16(3):243-51.

Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383(6602):707-10.

Bedogni B, Warneke JA, Nickoloff BJ, et al. Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest. 2008;118(11):3660-70.

Meurette O, Stylianou S, Rock R, et al. Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Res. 2009;69(12):5015-22.

Rangarajan A, Syal R, Selvarajah S, et al. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology. 2001;286(1):23-30.

Weijzen S, Rizzo P, Braid M, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med. 2002;8(9):979-86.

Zeng Q, Li S, Chepeha DB, et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005;8(1):13-23.

Joshi I, Minter LM, Telfer J, et al. Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood. 2009;113(8):1689-98.

Nickoloff BJ, Qin JZ, Chaturvedi V, et al. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ. 2002;9(8):842-55.

Di Giovanni V, Walker KA, Bushnell D, et al. Fibroblast growth factor receptor-Frs2alpha signaling is critical for nephron progenitors. Dev Biol. 2015;400(1):82-93.

Small D, Kovalenko D, Soldi R, et al. Notch activation suppresses fibroblast growth factor-dependent cellular transformation. J Biol Chem. 2003;278(18):16405-13.

Yoon K, Nery S, Rutlin ML, et al. Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors. J Neurosci. 2004;24(43):9497-506.

Liu ZJ, Shirakawa T, Li Y, et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol. 2003;23(1):14-25.

Shawber CJ, Funahashi Y, Francisco E, et al. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest. 2007;117(11):3369-82.

Zou Y, Cao Y, Yue Z, et al. Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function. Clin Exp Med. 2013;13(4):271-8.

Aguirre A, Rubio ME, Gallo V. Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature. 2010;467(7313):323-7.

Purow BW, Sundaresan TK, Burdick MJ, et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis. 2008;29(5):918-25.

Blokzijl A, Dahlqvist C, Reissmann E, et al. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol. 2003;163(4):723-8.

Dahlqvist C, Blokzijl A, Chapman G, et al. Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation. Development. 2003;130(24):6089-99.

Takizawa T, Ochiai W, Nakashima K, et al. Enhanced gene activation by Notch and BMP signaling cross-talk. Nucleic Acids Res. 2003;31(19):5723-31.

Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104):823-6.

Huang M, Chang A, Choi M, et al. Antagonistic interaction between Wnt and Notch activity modulates the regenerative capacity of a zebrafish fibrotic liver model. Hepatology. 2014;60(5):1753-66.

Li B, Jia Z, Wang T, et al. Interaction of Wnt/beta-catenin and notch signaling in the early stage of cardiac differentiation of P19CL6 cells. J Cell Biochem. 2012;113(2):629-39.

Casso DJ, Biehs B, Kornberg TB. A novel interaction between hedgehog and Notch promotes proliferation at the anterior-posterior organizer of the Drosophila wing. Genetics. 2011;187(2):485-99.

Xie G, Karaca G, Swiderska-Syn M, et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology. 2013;58(5):1801-13.

Liu S, Breit S, Danckwardt S, et al. Downregulation of Notch signaling by gamma-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines. Ann Hematol. 2009;88(7):613-21.

Grabher C, von Boehmer H, Look AT. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer. 2006;6(5):347-59.

Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J Exp Med. 2011;208(10):1931-5.

Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269-71.

Gallahan D, Kozak C, Callahan R. A new common integration region (int-3) for mouse mammary tumor virus on mouse chromosome 17. J Virol. 1987;61(1):218-20.

Brennan K, Clarke RB. Combining Notch inhibition with current therapies for breast cancer treatment. Ther Adv Med Oncol. 2013;5(1):17-24.

Rizzo P, Miao H, D'Souza G, et al. Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res. 2008;68(13):5226-35.

Wang Z, Li Y, Banerjee S, et al. Emerging role of Notch in stem cells and cancer. Cancer Lett. 2009;279(1):8-12.

Leong KG, Niessen K, Kulic I, et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 2007;204(12):2935-48.

Stylianou S, Clarke RB, Brennan K. Aberrant activation of notch signaling in human breast cancer. Cancer Res. 2006;66(3):1517-25.

Pece S, Serresi M, Santolini E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol. 2004;167(2):215-21.

Abravanel DL, Belka GK, Pan TC, et al. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J Clin Invest. 2015;125(6):2484-96.

Harrison H, Farnie G, Howell SJ, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 2010;70(2):709-18.

Reedijk M, Odorcic S, Chang L, et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 2005;65(18):8530-7.

O'Neill CF, Urs S, Cinelli C, et al. Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am J Pathol. 2007;171(3):1023-36.

Yamaguchi N, Oyama T, Ito E, et al. NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 2008;68(6):1881-8.

Reichrath J, Reichrath S. Notch-signaling and nonmelanoma skin cancer: an ancient friend, revisited. Adv Exp Med Biol. 2012;727:265-71.

Balint K, Xiao M, Pinnix CC, et al. Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest. 2005;115(11):3166-76.

Liu ZJ, Xiao M, Balint K, et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Res. 2006;66(8):4182-90.

Maillard I, Pear WS. Notch and cancer: best to avoid the ups and downs. Cancer Cell. 2003;3(3):203-5.

Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001;20(13):3427-36.

Devgan V, Mammucari C, Millar SE, et al. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev. 2005;19(12):1485-95.

Nguyen BC, Lefort K, Mandinova A, et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 2006;20(8):1028-42.

Nicolas M, Wolfer A, Raj K, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33(3):416-21.

George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53.

Wang NJ, Sanborn Z, Arnett KL, et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci USA. 2011;108(43):17761-6.

Sriuranpong V, Borges MW, Ravi RK, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001;61(7):3200-5.

Hu W, Lu C, Dong HH, et al. Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Res. 2011;71(18):6030-9.

Hernandez SL, Banerjee D, Garcia A, et al. Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis. Vasc Cell. 2013;5(1):17.

Dufraine J, Funahashi Y, Kitajewski J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 2008;27(38):5132-7.

Funahashi Y, Hernandez SL, Das I, et al. A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 2008;68(12):4727-35.

Li JL, Sainson RC, Shi W, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 2007;67(23):11244-53.

Noguera-Troise I, Daly C, Papadopoulos NJ, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444(7122):1032-7.

Ridgway J, Zhang G, Wu Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444(7122):1083-7.

Yan M, Callahan CA, Beyer JC, et al. Chronic DLL4 blockade induces vascular neoplasms. Nature. 2010;463(7282):E6-7.

Debeb BG, Cohen EN, Boley K, et al. Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. Breast Cancer Res Treat. 2012;134(2):495-510.

Simmons MJ, Serra R, Hermance N, et al. NOTCH1 inhibition in vivo results in mammary tumor regression and reduced mammary tumorsphere-forming activity in vitro. Breast Cancer Res. 2012;14(5):R126.

Zhu TS, Costello MA, Talsma CE, et al. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 2011;71(18):6061-72.

Aste-Amezaga M, Zhang N, Lineberger JE, et al. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One. 2010;5(2):e9094.

Yen WC, Fischer MM, Axelrod F, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 2015;21(9):2084-95.

Scehnet JS, Jiang W, Kumar SR, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood. 2007;109(11):4753-60.

Reynolds ND, Lukacs NW, Long N, et al. Delta-like ligand 4 regulates central nervous system T cell accumulation during experimental autoimmune encephalomyelitis. J Immunol. 2011;187(5):2803-13.

Takebe N, Nguyen D, Yang SX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther. 2014;141(2):140-9.

Hayashi I, Takatori S, Urano Y, et al. Neutralization of the gamma-secretase activity by monoclonal antibody against extracellular domain of nicastrin. Oncogene. 2012;31(6):787-98.

Small D, Kovalenko D, Kacer D, et al. Soluble Jagged 1 represses the function of its transmembrane form to induce the formation of the Src-dependent chord-like phenotype. J Biol Chem. 2001;276(34):32022-30.

Nichol D, Shawber C, Fitch MJ, et al. Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7. Blood. 2010;116(26):6133-43.

Kolb EA, Gorlick R, Keir ST, et al. Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a gamma-secretase inhibitor targeting notch signaling. Pediatr Blood Cancer. 2012;58(5):815-8.

Luistro L, He W, Smith M, et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 2009;69(19):7672-80.

He W, Luistro L, Carvajal D, et al. High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the gamma-secretase inhibitor, RO4929097. Mol Oncol. 2011;5(3):292-301.

Huynh C, Poliseno L, Segura MF, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One. 2011;6(9):e25264.

Nair JS, Sheikh T, Ho AL, et al. PTEN regulates sensitivity of melanoma cells to RO4929097, the gamma-secretase inhibitor. Anticancer Res. 2013;33(4):1307-16.

Saito N, Fu J, Zheng S, et al. A high Notch pathway activation predicts response to gamma secretase inhibitors in proneural subtype of glioma tumor-initiating cells. Stem Cells. 2014;32(1):301-12.

Dantas-Barbosa C, Bergthold G, Daudigeos-Dubus E, et al. Inhibition of the NOTCH pathway using gamma-secretase inhibitor RO4929097 has limited antitumor activity in established glial tumors. Anticancer Drugs. 2015;26(3):272-83.

LoConte NK, Razak AR, Ivy P, et al. A multicenter phase 1 study of gamma -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors. Invest New Drugs. 2015;33(1):169-76.

Wei P, Walls M, Qiu M, et al. Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010;9(6):1618-28.

Lopez-Guerra M, Xargay-Torrent S, Rosich L, et al. The gamma-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells. Leukemia. 2015;29(1):96-106.

Samon JB, Castillo-Martin M, Hadler M, et al. Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol Cancer Ther. 2012;11(7):1565-75.

Zhang CC, Yan Z, Zong Q, et al. Synergistic effect of the gamma-secretase inhibitor PF-03084014 and docetaxel in breast cancer models. Stem Cells Transl Med. 2013;2(3):233-42.

Grottkau BE, Chen XR, Friedrich CC, et al. DAPT enhances the apoptosis of human tongue carcinoma cells. Int J Oral Sci. 2009;1(2):81-9.

Jing W, Xiong Z, Cai X, et al. Effects of gamma-secretase inhibition on the proliferation and vitamin D(3) induced osteogenesis in adipose derived stem cells. Biochem Biophys Res Commun. 2010;392(3):442-7.

Mori M, Miyamoto T, Yakushiji H et al. Effects of N-[N-(3, 5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) on cell proliferation and apoptosis in Ishikawa endometrial cancer cells. Hum Cell. 2012;25(1):9-15.

Li LC, Peng Y, Liu YM, et al. Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by gamma-secretase inhibitor DAPT. Oncol Lett. 2014;7(6):2160-4.

Wang M, Ma X, Wang J, et al. Pretreatment with the gamma-secretase inhibitor DAPT sensitizes drug-resistant ovarian cancer cells to cisplatin by downregulation of Notch signaling. Int J Oncol. 2014;44(4):1401-9.

Khazaei M, Kalantari E, Saeidi H, et al. Gamma-secretase inhibitor does not modulate angiogenesis in colon adenocarcinoma in obese mice. Bratisl Lek Listy. 2015;116(4):248-51.

Tammam J, Ware C, Efferson C, et al. Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol. 2009;158(5):1183-95.

Pandya K, Meeke K, Clementz AG, et al. Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br J Cancer. 2011;105(6):796-806.

Ramakrishnan V, Ansell S, Haug J, et al. MRK003, a gamma-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma. Leukemia. 2012;26(2):340-8.

Plentz R, Park JS, Rhim AD, et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology. 2009;136(5):1741-9e6.

Timme CR, Gruidl M, Yeatman TJ. Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells. Apoptosis. 2013;18(10):1163-74.

De Keersmaecker K, Lahortiga I, Mentens N, et al. In vitro validation of gamma-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. Haematologica. 2008;93(4):533-42.

Meng X, Matlawska-Wasowska K, Girodon F, et al. GSI-I (Z-LLNle-CHO) inhibits gamma-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia. Leukemia. 2011;25(7):1135-46.

Schott AF, Landis MD, Dontu G, et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res. 2013;19(6):1512-24.

Albain K, Czerlanis C, Zlobin A, et al. Modulation of cancer and stem cell biomarkers by the notch inhibitor MK-0725 added to endocrine therapy for early stage ER+ breast cancer. Cancer Research. 2011;71(24 Supplement):S1-5.

Krop I, Demuth T, Guthrie T, et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol. 2012;30(19):2307-13.

Wu Y, Cain-Hom C, Choy L, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010;464(7291):1052-7.

Moellering RE, Cornejo M, Davis TN, et al. Direct inhibition of the NOTCH transcription factor complex. Nature. 2009;462(7270):182-8.

Epenetos A, Kosparou C, Stylianou S. Inhibition of Notch signaling for the treatment of human carcinomas. Proceedings of the American Association of Cancer Research. 2009;18-22.


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