Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Biotechnology Open Access 24 November 2022
Comprehensive characterization of posttranscriptional impairment-related 3′-UTR mutations in 2413 whole genomes of cancer patients
npj Genomic Medicine Open Access 02 June 2022
Signal Transduction and Targeted Therapy Open Access 24 March 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Morgan, T. H. The theory of the gene. Am. Naturalist. 609, 513–544 (1917).
Artavanis-Tsakonas, S., Muskavitch, M. A. & Yedvobnick, B. Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 80, 1977–1981 (1983).
Wharton, K. A., Johansen, K. M., Xu, T. & Artavanis-Tsakonas, S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF- like repeats. Cell 43, 567–581 (1985).
Yochem, J., Weston, K. & Greenwald, I. The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch. Nature 335, 547–550 (1988).
Yochem, J. & Greenwald, I. glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins. Cell 58, 553–563 (1989).
Kopan, R. Notch signaling. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a011213 (2012).
Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).
Ladi, E. 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. 170, 983–992 (2005).
Andersson, E. R. & Lendahl, U. Therapeutic modulation of Notch signalling–are we there yet? Nat. Rev. Drug Discov. 13, 357–378 (2014). This article is a comprehensive review of therapeutic targeting of Notch signalling in multiple indications.
Kovall, R. A., Gebelein, B., Sprinzak, D. & Kopan, R. The canonical notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Dev. Cell 41, 228–241 (2017).
Ellisen, L. W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991). This is the first demonstration of oncogenic activity of NOTCH1 in humans.
Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).
Weng, A. P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20, 2096–2109 (2006).
Fabbri, G. et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208, 1389–1401 (2011).
Rossi, D. et al. The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. J. Exp. Med. 209, 1537–1551 (2012).
Robinson, D. R. et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat. Med. 17, 1646–1651 (2011).
Dang, T. P. et al. Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J. Natl Cancer Inst. 92, 1355–1357 (2000).
Ho, A. S. et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J. Clin. Invest. 129, 4276–4289 (2019).
Espinoza, I. & Miele, L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 341, 41–45 (2013).
Espinoza, I., Pochampally, R., Xing, F., Watabe, K. & Miele, L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. OncoTargets Ther. 6, 1249–1259 (2013).
Sosa Iglesias, V., Giuranno, L., Dubois, L. J., Theys, J. & Vooijs, M. Drug resistance in non-small cell lung cancer: a potential for NOTCH targeting? Front. Oncol. 8, 267 (2018).
Meurette, O. & Mehlen, P. Notch signaling in the tumor microenvironment. Cancer Cell 34, 536–548 (2018).
Mollen, E. W. J. et al. Moving breast cancer therapy up a notch. Front. Oncol. 8, 518 (2018).
Arruga, F., Vaisitti, T. & Deaglio, S. The NOTCH pathway and its mutations in mature B cell malignancies. Front. Oncol. 8, 550 (2018).
Saygin, C., Matei, D., Majeti, R., Reizes, O. & Lathia, J. D. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell 24, 25–40 (2019).
Ceccarelli, S. et al. Notch3 targeting: a novel weapon against ovarian cancer stem cells. Stem Cell Int. 2019, 6264931 (2019).
Xiu, M. X. & Liu, Y. M. The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. Am. J. Cancer Res. 9, 837–854 (2019).
Giuli, M. V., Giuliani, E., Screpanti, I., Bellavia, D. & Checquolo, S. Notch signaling activation as a hallmark for triple-negative breast cancer subtype. J. Oncol. 2019, 8707053 (2019).
Gersey, Z. et al. Therapeutic targeting of the notch pathway in glioblastoma multiforme. World Neurosurg. 131, 252–263.e252 (2019).
Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/nrclinonc.2015.61 (2015). This review covers the challenges and opportunities in targeting master developmental pathways in cancer stem cells.
Bray, S. J. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 17, 722–735 (2016).
Espinoza, I. & Miele, L. Notch inhibitors for cancer treatment. Pharmacol Ther. https://doi.org/10.1016/j.pharmthera.2013.02.003 (2013).
Carrieri, F. A. et al. CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock. EMBO Rep. 20, e46436 (2019).
Aster, J. C., Pear, W. S. & Blacklow, S. C. The varied roles of notch in cancer. Annu. Rev. Pathol. 12, 245–275 (2017). This article provides a comprehensive review of the multiple roles of Notch signalling in cancer.
Vinson, K. E., George, D. C., Fender, A. W., Bertrand, F. E. & Sigounas, G. The Notch pathway in colorectal cancer. Int. J. Cancer 138, 1835–1842 (2016).
Kwon, O. J. et al. Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J. Clin. Invest. 126, 2626–2641 (2016).
Bazzoni, R. & Bentivegna, A. Role of Notch signaling pathway in glioblastoma pathogenesis. Cancers https://doi.org/10.3390/cancers11030292 (2019).
Tamagnone, L., Zacchigna, S. & Rehman, M. Taming the Notch transcriptional regulator for cancer therapy. Molecules https://doi.org/10.3390/molecules23020431 (2018).
Thurston, G. & Kitajewski, J. VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br. J. Cancer 99, 1204–1209 (2008). This article describes the interplay between VEGF and Notch signalling in tumour angiogenesis.
Radtke, F. & Raj, K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat. Rev. Cancer 3, 756–767 (2003).
Ranganathan, P., Weaver, K. L. & Capobianco, A. J. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat. Rev. Cancer 11, 338–351 (2011).
Nguyen, B. C. et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 20, 1028–1042 (2006).
Koch, U. & Radtke, F. Notch and cancer: a double-edged sword. Cell. Mol. Life Sci. 64, 2746–2762 (2007).
Lowell, S., Jones, P., Le Roux, I., Dunne, J. & Watt, F. M. Stimulation of human epidermal differentiation by Delta–Notch signalling at the boundaries of stem-cell clusters. Curr. Biol. 10, 491–500 (2000).
Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001).
Klinakis, A. et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473, 230–233 (2011).
Zage, P. E. et al. Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr. Blood Cancer 58, 682–689 (2012).
Hernandez Tejada, F. N., Galvez Silva, J. R. & Zweidler-McKay, P. A. The challenge of targeting notch in hematologic malignancies. Front. Pediatr. 2, 54 (2014).
Viatour, P. et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J. Exp. Med. 208, 1963–1976 (2011).
Ye, Y. C. et al. NOTCH Signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma. Cancer Res. 79, 4160–4172 (2019).
Fang, S. et al. Lymphoid enhancer-binding factor-1 promotes stemness and poor differentiation of hepatocellular carcinoma by directly activating the NOTCH pathway. Oncogene 38, 4061–4074 (2019).
Fukusumi, T. & Califano, J. A. The NOTCH pathway in head and neck squamous cell carcinoma. J. Dent. Res. 97, 645–653 (2018).
Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).
Lim, J. S. et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature 545, 360–364 (2017). This study is the first demonstration that Notch can have tumour-suppressive and oncogenic functions in different, interacting cell populations in the same tumour.
Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).
Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).
Fan, X. et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 66, 7445–7452 (2006).
Armstrong, F. et al. NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood 113, 1730–1740 (2009).
Sikandar, S. S. et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 70, 1469–1478 (2010).
Harrison, H., Farnie, G., Brennan, K. R. & Clarke, R. B. Breast cancer stem cells: something out of notching? Cancer Res. 70, 8973–8976 (2010).
Hassan, K. A. et al. Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin. Cancer Res. 19, 1972–1980 (2013).
Crabtree, J. S. & Miele, L. Breast cancer stem cells. Biomedicines https://doi.org/10.3390/biomedicines6030077 (2018).
Harrison, H. et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 70, 709–718 (2010).
Robinson, D. R. et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45, 1446–1451 (2013).
Toy, W. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45, 1439–1445 (2013).
Fuqua, S. A., Gu, G. & Rechoum, Y. Estrogen receptor (ER) alpha mutations in breast cancer: hidden in plain sight. Breast Cancer Res. Treat. 144, 11–19 (2014).
Gelsomino, L. et al. Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation in breast cancer cell lines. Cancer Lett. 428, 12–20 (2018).
Hirata, N. et al. Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat. Commun. 5, 4806 (2014). This study suggests a potentially druggable, ligand-independent Notch activation mechanism in breast cancer stem cells.
Mao, J. et al. ShRNA targeting Notch1 sensitizes breast cancer stem cell to paclitaxel. Int. J. Biochem. Cell Biol. 45, 1064–1073 (2013).
Bhola, N. E. et al. Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and notch-dependent cancer stem cell population. Cancer Res. 76, 440–452 (2016). This study implicates Notch-dependent CSCs in mTOR complex 1/2 resistance in TNBC.
Pandya, K. et al. Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br. J. Cancer 105, 796–806 (2011). This study implicates Notch signalling in trastuzumab resistance.
Shah, D. et al. Inhibition of HER2 increases JAGGED1-dependent breast cancer stem cells: role for membrane JAGGED1. Clin. Cancer Res. 24, 4566–4578 (2018).
Baker, A. et al. Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival. Oncogene 37, 4489–4504 (2018).
Luo, H. et al. Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET. Oncotarget 9, 18885–18895 (2018).
Man, J. et al. Hypoxic induction of vasorin regulates Notch1 turnover to maintain glioma stem-like cells. Cell Stem Cell 22, 104–118 e106 (2018).
Tsao, P. N. et al. Gamma-secretase activation of notch signaling regulates the balance of proximal and distal fates in progenitor cells of the developing lung. J. Biol. Chem. 283, 29532–29544 (2008).
Westhoff, B. et al. Alterations of the Notch pathway in lung cancer. Proc. Natl Acad. Sci. USA 106, 22293–22298 (2009).
Eliasz, S. et al. Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29, 2488–2498 (2010).
Chen, Y. et al. Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res. 67, 7954–7959 (2007).
Arasada, R. R., Amann, J. M., Rahman, M. A., Huppert, S. S. & Carbone, D. P. EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling. Cancer Res. 74, 5572–5584 (2014).
Arasada, R. R. et al. Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC. Nat. Commun. 9, 3198 (2018). This study supports a novel non-canonical function of NOTCH3 via β-catenin signalling in TKI resistance in NSCLC.
Weis, S. M. & Cheresh, D. A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17, 1359–1370 (2011).
Pitulescu, M. E. et al. Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat. Cell Biol. 19, 915–927 (2017).
Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).
Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Novartis. Found. Symp. 283, 106–120 (2007).
Jia, X. et al. A humanized anti-DLL4 antibody promotes dysfunctional angiogenesis and inhibits breast tumor growth. Sci. Rep. 6, 27985 (2016).
Chiorean, E. G. et al. A phase I first-in-human study of enoticumab (REGN421), a fully human delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clin. Cancer Res. 21, 2695–2703 (2015).
Rizzo, P. et al. The role of notch in the cardiovascular system: potential adverse effects of investigational notch inhibitors. Front. Oncol. 4, 384 (2014).
Yan, M. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010).
Liu, Z. et al. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J. Clin. Invest. 121, 800–808 (2011).
Kangsamaksin, T. et al. NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth. Cancer Discov. 5, 182–197 (2015).
Ayaz, F. & Osborne, B. A. Non-canonical notch signaling in cancer and immunity. Front. Oncol. 4, 345 (2014). This is a comprehensive review of non-canonical Notch signalling.
Minter, L. M. & Osborne, B. A. Canonical and non-canonical Notch signaling in CD4+ T cells. Curr. Top. Microbiol. Immunol. 360, 99–114 (2012).
Hossain, F. et al. Notch signaling in myeloid cells as a regulator of tumor immune responses. Front. Immunol. 9, 1288 (2018).
Vijayaraghavan, J. & Osborne, B. A. Notch and T Cell Function - a complex tale. Adv. Exp. Med. Biol. 1066, 339–354 (2018).
Janghorban, M., Xin, L., Rosen, J. M. & Zhang, X. H. Notch signaling as a regulator of the tumor immune response: to target or not to target? Front. Immunol. 9, 1649 (2018).
Tsukumo, S. I. & Yasutomo, K. Regulation of CD8+ T cells and antitumor immunity by notch signaling. Front. Immunol. 9, 101 (2018). Tsukumo and Yasutomo (2018), Cho et al. (2009), Maekawa et al. (2008) and Sugimoto et al. (2010) describe the role of Notch signalling in promoting CD8+ T cell-mediated tumour immunity.
Cho, O. H. et al. Notch regulates cytolytic effector function in CD8+ T cells. J. Immunol. 182, 3380–3389 (2009).
Maekawa, Y. et al. Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat. Immunol. 9, 1140–1147 (2008).
Sugimoto, K. et al. Notch2 signaling is required for potent antitumor immunity in vivo. J. Immunol. 184, 4673–4678 (2010).
Kijima, M. et al. Jagged1 suppresses collagen-induced arthritis by indirectly providing a negative signal in CD8+ T cells. J. Immunol. 182, 3566–3572 (2009).
Huang, Y. et al. Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res. 71, 6122–6131 (2011).
Biktasova, A. K. et al. Multivalent forms of the notch ligand DLL-1 enhance antitumor T-cell immunity in lung cancer and improve efficacy of EGFR-targeted therapy. Cancer Res. 75, 4728–4741 (2015).
Kondo, T. et al. Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy. Nat. Commun. 8, 15338 (2017).
Steinbuck, M. P. & Winandy, S. A review of notch processing with new insights into ligand-independent notch signaling in T-cells. Front. Immunol. 9, 1230 (2018). Steinbuck and Winandy (2018) and Steinbuck et al. (2018) describe endosomal, ligand-independent Notch activation in the context of T cell activation.
Steinbuck, M. P., Arakcheeva, K. & Winandy, S. Novel TCR-mediated mechanisms of notch activation and signaling. J. Immunol. 200, 997–1007 (2018).
Sorrentino, C. et al. Adenosine A2A receptor stimulation inhibits TCR-induced Notch1 activation in CD8+T-cells. Front. Immunol. 10, 162 (2019).
Congreve, M., Brown, G. A., Borodovsky, A. & Lamb, M. L. Targeting adenosine A2A receptor antagonism for treatment of cancer. Expert Opin. Drug Discov. 13, 997–1003 (2018).
Sierra, R. A. et al. Rescue of notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. Cancer Immunol. Res. 2, 800–811 (2014).
Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167, 419–432 (2016).
Cho, J. H. et al. Engineering Axl specific CAR and SynNotch receptor for cancer therapy. Sci. Rep. 8, 3846 (2018). This study demonstrates the feasibility of the synNotch receptor approach in adoptive cell therapy for cancer.
Peng, D. et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH Cross-talk signaling. Cancer Res. 76, 3156–3165 (2016). Peng et al. (2016) and Shen et al. (2017) describe Notch-mediated crosstalk between stroma and breast cancer stem cells.
Shen, Q. et al. Notch shapes the innate immunophenotype in breast cancer. Cancer Discov. 7, 1320–1335 (2017).
Yeong, J., Thike, A. A., Tan, P. H. & Iqbal, J. Identifying progression predictors of breast ductal carcinoma in situ. J. Clin. Pathol. 70, 102–108 (2017).
Strell, C. et al. Impact of epithelial-stromal interactions on peritumoral fibroblasts in ductal carcinoma in situ. J. Natl Cancer Inst. 111, 983–995 (2019).
Sierra, R. A. et al. Anti-jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. Cancer Res. 77, 5628–5638 (2017). This study supports the potential of Jagged 1 as a therapeutic target in cancer immunotherapy.
Santagata, S. et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 64, 6854–6857 (2004).
Zhu, H., Zhou, X., Redfield, S., Lewin, J. & Miele, L. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. Am. J. Transl Res. 5, 368–378 (2013).
Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).
Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747 (2017). Sethi et al. (2011) and Zheng et al. (2017) support the potential of Jagged 1 as a therapeutic target in metastasis.
Houde, C. et al. Over-expression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood 104, 3697–3704 (2004).
Colombo, M. et al. Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche. Oncotarget 7, 56013–56029 (2016).
Colombo, M. et al. Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance. Haematologica https://doi.org/10.3324/haematol.2019.221077 (2019).
Leontovich, A. A. et al. NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Res. 20, 105 (2018).
Choy, L. et al. Constitutive NOTCH3 signaling promotes the growth of basal breast cancers. Cancer Res. 77, 1439–1452 (2017).
Imbimbo, B. P. et al. Therapeutic intervention for Alzheimer’s disease with gamma-secretase inhibitors: still a viable option? Expert Opin. Invest. Drugs 20, 325–341 (2011).
Ran, Y. et al. gamma-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol. Med. 9, 950–966 (2017). This study highlights the different pharmacological properties and anti-CSC activity of different classes of investigational GSIs.
Schott, A. F. et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin. Cancer Res. 19, 1512–1524 (2013).
Riccio, O. et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 9, 377–383 (2008).
Samon, J. B. et al. Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol. Cancer Ther. 11, 1565–1575 (2012).
Yun, J. et al. Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis 2, e60 (2013).
Dumortier, A. et al. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin. PloS ONE 5, e9258 (2010).
Papayannidis, C. et al. A phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J. 5, e350 (2015).
Locatelli, M. A. et al. Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer. Oncotarget 8, 2320–2328 (2017).
Kummar, S. et al. Clinical activity of the gamma-secretase inhibitor PF-03084014 in Adults with desmoid tumors (aggressive fibromatosis). J. Clin. Oncol. 35, 1561–1569 (2017).
Villalobos, V. M. et al. Long-term follow-up of desmoid fibromatosis treated with PF-03084014, an oral gamma secretase inhibitor. Ann. Surg. Oncol. 25, 768–775 (2018).
Takahashi, T., Prensner, J. R., Robson, C. D., Janeway, K. A. & Weigel, B. J. Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: report of four pediatric/young adult cases. Pediatr Blood Cancer https://doi.org/10.1002/pbc.28636 (2020).
Morgan, K. M. et al. Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma. Mol. Cancer Ther. 16, 2759–2769 (2017).
Massard, C. et al. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann. Oncol. 29, 1911–1917 (2018).
Moss, M. L. & Minond, D. Recent advances in ADAM17 research: a promising target for cancer and inflammation. Mediators Inflamm. 2017, 9673537 (2017).
Malapeira, J., Esselens, C., Bech-Serra, J. J., Canals, F. & Arribas, J. ADAM17 (TACE) regulates TGFbeta signaling through the cleavage of vasorin. Oncogene 30, 1912–1922 (2011).
Li, D. D. et al. A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5-Fluorouracil by reversing Notch and epithelial-mesenchymal transition in vitro and in vivo. Cell Prolif. 51, e12480 (2018).
Wu, Y. et al. Therapeutic antibody targeting of individual Notch receptors. Nature 464, 1052–1057 (2010).
Aste-Amezaga, M. et al. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS ONE 5, e9094 (2010).
Agnusdei, V. et al. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia 28, 278–288 (2014).
Agnusdei, V. et al. Dissecting molecular mechanisms of resistance to Notch1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts. Haematologica https://doi.org/10.3324/haematol.2019.217687 (2019).
Sharma, A. et al. A novel monoclonal antibody against notch1 targets leukemia-associated mutant notch1 and depletes therapy resistant cancer stem cells in solid tumors. Sci. Rep. 5, 11012 (2015).
Bernasconi-Elias, P. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016).
Proia, T. et al. 23814, an inhibitory antibody of ligand-mediated Notch1 activation, modulates angiogenesis and inhibits tumor growth without gastrointestinal toxicity. Mol. Cancer Ther. 14, 1858–1867 (2015).
Yen, W. C. et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin. Cancer Res. 21, 2084–2095 (2015).
Smith, D. C. et al. A phase 1 dose escalation and expansion study of tarextumab (OMP-59R5) in patients with solid tumors. Invest. N. Drugs 37, 722–730 (2019).
Hu, Z. I. et al. A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer. Cancer Med. 8, 5148–5157 (2019).
Hu, S. et al. Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aag0339 (2017).
Rosen, L. S. et al. A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors. Invest. New Drugs https://doi.org/10.1007/s10637-019-00754-y (2019).
Filipovic, A. et al. Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells. Breast Cancer Res. Treat. 148, 455–462 (2014).
Smith, D. C. et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin. Cancer Res. 20, 6295–6303 (2014).
McKeage, M. J. et al. Phase IB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC. Target. Oncol. 13, 89–98 (2018).
Coleman, R. L. et al. Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: the SIERRA open-label phase Ib trial. Gynecol. Oncol. https://doi.org/10.1016/j.ygyno.2020.01.042 (2020).
Huang, J. et al. Dll4 inhibition plus aflibercept markedly reduces ovarian tumor growth. Mol. Cancer Ther. 15, 1344–1352 (2016).
Jimeno, A. et al. A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Invest. N. Drugs 37, 461–472 (2019).
Lafkas, D. et al. Therapeutic antibodies reveal notch control of transdifferentiation in the adult lung. Nature 528, 127–131 (2015).
Pandya, K. et al. PKCalpha attenuates jagged-1-mediated notch signaling in ErbB-2-positive breast cancer to reverse trastuzumab resistance. Clin. Cancer Res. 22, 175–186 (2016).
Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci. Transl Med. 7, 302ra136 (2015).
Morgensztern, D. et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin. Cancer Res. 25, 6958–6966 (2019).
Crabtree, J. S., Singleton, C. S. & Miele, L. Notch signaling in neuroendocrine tumors. Front. Oncol. 6, 94 (2016).
Owen, D. H. et al. DLL3: an emerging target in small cell lung cancer. J. Hematol. Oncol. 12, 61 (2019).
Golde, T. E., Koo, E. H., Felsenstein, K. M., Osborne, B. A. & Miele, L. gamma-Secretase inhibitors and modulators. Biochim. Biophys. Acta 1828, 2898–2907 (2013).
Habets, R. A. et al. Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aau6246 (2019).
Borgegard, T. et al. Alzheimer’s disease: presenilin 2-sparing gamma-secretase inhibition is a tolerable Abeta peptide-lowering strategy. J. Neurosci. 32, 17297–17305 (2012).
Bursavich, M. G., Harrison, B. A. & Blain, J. F. Gamma secretase modulators: new Alzheimer’s drugs on the horizon? J. Med. Chem. 59, 7389–7409 (2016).
Wagner, S. L. et al. Pharmacological and toxicological properties of the potent oral gamma-secretase modulator BPN-15606. J. Pharmacol. Exp. Ther. 362, 31–44 (2017).
Kounnas, M. Z., Lane-Donovan, C., Nowakowski, D. W., Herz, J. & Comer, W. T. NGP 555, a gamma-secretase modulator, lowers the amyloid biomarker, Abeta42, in cerebrospinal fluid while preventing Alzheimer’s disease cognitive decline in rodents. Alzheimers Dement. 3, 65–73 (2017).
Kukar, T. L. et al. Substrate-targeting gamma-secretase modulators. Nature 453, 925–929 (2008).
Kang, M. S. et al. Modulation of lipid kinase PI4KIIalpha activity and lipid raft association of presenilin 1 underlies gamma-secretase inhibition by ginsenoside (20S)-Rg3. J. Biol. Chem. 288, 20868–20882 (2013).
Platonova, N. et al. Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening. PLoS ONE 12, e0182640 (2017).
Gangrade, A. et al. Preferential inhibition of Wnt/beta-catenin signaling by novel benzimidazole compounds in triple-negative breast cancer. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19051524 (2018).
Perron, A. et al. Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone. J. Biol. Chem. 293, 8285–8294 (2018).
Urech-Varenne, C., Radtke, F. & Heinis, C. Phage selection of bicyclic peptide ligands of the Notch1 receptor. ChemMedChem 10, 1754–1761 (2015).
Moellering, R. E. et al. Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182–188 (2009). This study is the first demonstration that the Notch transcriptional complex is potentially druggable.
Opacak-Bernardi, T., Ryu, J. S. & Raucher, D. Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells. J. Drug Target. 25, 523–531 (2017).
Ding, W. et al. Effect of lenalidomide on the human gastric cancer cell line SGC7901/vincristine Notch signaling. J. Cancer Res. Ther. 14, S237–S242 (2018).
Pinazza, M. et al. Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells. Oncogene 37, 3839–3851 (2018).
Zhong, L. et al. Histone deacetylase 5 promotes the proliferation and invasion of lung cancer cells. Oncol. Rep. 40, 2224–2232 (2018).
Granit, R. Z. et al. Regulation of cellular heterogeneity and rates of symmetric and asymmetric divisions in triple-negative breast cancer. Cell Rep. 24, 3237–3250 (2018).
Ponnurangam, S. et al. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget 7, 3217–3232 (2016).
Guerrero-Hernandez, A., Dagnino-Acosta, A. & Verkhratsky, A. An intelligent sarco-endoplasmic reticulum Ca2+ store: release and leak channels have differential access to a concealed Ca2+ pool. Cell Calcium 48, 143–149 (2010).
Roti, G. et al. Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. Cancer Cell 23, 390–405 (2013).
Roti, G. et al. Leukemia-specific delivery of mutant NOTCH1 targeted therapy. J. Exp. Med. 215, 197–216 (2018).
Suisse, A. & Treisman, J. E. Reduced SERCA function preferentially affects Wnt signaling by retaining E-cadherin in the endoplasmic reticulum. Cell Rep. 26, 322–329 e323 (2019).
Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).
Bruckner, K., Perez, L., Clausen, H. & Cohen, S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406, 411–415 (2000).
Schneider, M. et al. Inhibition of delta-induced notch signaling using fucose analogs. Nat. Chem. Biol. 14, 65–71 (2018).
Takeuchi, H. et al. Two novel protein O-glucosyltransferases that modify sites distinct from POGLUT1 and affect Notch trafficking and signaling. Proc. Natl Acad. Sci. USA 115, E8395–E8402 (2018).
Tutar, L., Tutar, E. & Tutar, Y. MicroRNAs and cancer; an overview. Curr. Pharm. Biotechnol. 15, 430–437 (2014).
Chen, J. et al. miR-598 inhibits metastasis in colorectal cancer by suppressing JAG1/Notch2 pathway stimulating EMT. Exp. Cell Res. 352, 104–112 (2017).
Shui, Y. et al. miR-130b-3p inhibits cell invasion and migration by targeting the Notch ligand Delta-like 1 in breast carcinoma. Gene 609, 80–87 (2017).
Jin, Y. et al. Overcoming stemness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling. Int. J. Biol. Macromol. 117, 445–453 (2018).
Pan, Y. et al. Lentivirus-mediated overexpression of miR-124 suppresses growth and invasion by targeting JAG1 and EZH2 in gastric cancer. Oncol. Lett. 15, 7450–7458 (2018).
Shin, V. Y. et al. MiR-92 suppresses proliferation and induces apoptosis by targeting EP4/Notch1 axis in gastric cancer. Oncotarget 9, 24209–24220 (2018).
Bettinsoli, P., Ferrari-Toninelli, G., Bonini, S. A., Prandelli, C. & Memo, M. Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma. BMC Cancer 17, 352 (2017).
Hanna, J., Hossain, G. S. & Kocerha, J. The potential for microRNA therapeutics and clinical research. Front. Genet. 10, 478 (2019).
Salvador-Reyes, L. A. & Luesch, H. Biological targets and mechanisms of action of natural products from marine cyanobacteria. Nat. Prod. Rep. 32, 478–503 (2015).
Thomford, N. E. et al. Natural products for drug discovery in the 21st century: innovations for novel drug discovery. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19061578 (2018).
Cao, Y. et al. Cinobufagin induces apoptosis of osteosarcoma cells through inactivation of Notch signaling. Eur. J. Pharmacol. 794, 77–84 (2017).
Yu, L. et al. Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling. Oncotarget 7, 33055–33068 (2016).
Dai, G. et al. The synergistic antitumor effect of cinobufagin and cisplatin in human osteosarcoma cell line in vitro and in vivo. Oncotarget 8, 85150–85168 (2017).
Kiesel, V. A. & Stan, S. D. Diallyl trisulfide, a chemopreventive agent from Allium vegetables, inhibits alpha-secretases in breast cancer cells. Biochem. Biophys. Res. Commun. 484, 833–838 (2017).
Chen, D. et al. Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Cell Stem Cell 20, 621–634 e626 (2017).
Ohtaka, M., Itoh, M. & Tohda, S. BMI1 inhibitors Down-regulate NOTCH signaling and suppress proliferation of acute leukemia cells. Anticancer Res. 37, 6047–6053 (2017).
Arai, M. A. et al. The notch inhibitors isolated from nerium indicum. J. Nat. Prod. 81, 1235–1240 (2018).
Arai, M. A. et al. The Notch inhibitor cowanin accelerates nicastrin degradation. Sci. Rep. 8, 5376 (2018).
Fiorillo, M. et al. Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism. Biochim. Biophys. Acta Bioenerg. 1859, 984–996 (2018).
Su, G., Chen, H. & Sun, X. Baicalein suppresses non small cell lung cancer cell proliferation, invasion and Notch signaling pathway. Cancer Biomark 22, 13–18 (2018).
Zhang, J. et al. Paeoniflorin influences breast cancer cell proliferation and invasion via inhibition of the Notch1 signaling pathway. Mol. Med. Rep. 17, 1321–1325 (2018).
Reiter, R. J. et al. Melatonin, a full service anti-cancer agent: inhibition of initiation, progression and metastasis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18040843 (2017).
Zheng, X. et al. Melatonin inhibits glioblastoma stem-like cells through suppression of EZH2-NOTCH1 signaling axis. Int. J. Biol. Sci. 13, 245–253 (2017).
Rajasinghe, L. D., Pindiprolu, R. H. & Gupta, S. V. Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-kappaB, uPA activator, and MMP-9. OncoTargets Ther. 11, 4301–4314 (2018).
Bommareddy, P. K., Patel, A., Hossain, S. & Kaufman, H. L. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am. J. Clin. Dermatol. 18, 1–15 (2017).
Mato-Berciano, A. et al. A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel. Oncotarget 8, 22700–22715 (2017). This study is the first example of Notch-targeted cancer virotherapy.
Keeler, A. M. & Flotte, T. R. Recombinant adeno-associated virus gene therapy in light of luxturna (and Zolgensma and Glybera): where are we, and how did we get here? Annu. Rev. Virol. 6, 601–621 (2019).
Xu, K. et al. Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell 21, 626–641 (2012).
Yeh, C. H., Bellon, M. & Nicot, C. FBXW7: a critical tumor suppressor of human cancers. Mol. Cancer 17, 115 (2018).
Sailo, B. L. et al. FBXW7 in cancer: what has been unraveled thus far? Cancers https://doi.org/10.3390/cancers11020246 (2019).
Jenkins, R. W. et al. Ex Vivo profiling of PD-1 blockade using organotypic tumor spheroids. Cancer Discov. 8, 196–215 (2018).
Britton, G. J. et al. PKCtheta links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton. eLife https://doi.org/10.7554/eLife.20003 (2017).
Kim, J. & Sage, J. Taking SCLC on a bad LSD(1) trip one NOTCH further. Trends Mol. Med. https://doi.org/10.1016/j.molmed.2019.02.009 (2019).
Weinmaster, G. & Fischer, J. A. Notch ligand ubiquitylation: what is it good for? Dev. Cell 21, 134–144 (2011).
Conner, S. D. Regulation of notch signaling through intracellular transport. Int. Rev. Cell Mol. Biol. 323, 107–127 (2016).
Gordon, W. R. et al. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14, 295–300 (2007).
Groot, A. J. & Vooijs, M. A. The role of Adams in notch signaling. Adv. Exp. Med. Biol. 727, 15–36 (2012).
Lu, P. et al. Three-dimensional structure of human γ-secretase. Nature 512, 166 (2014).
Steiner, H., Fluhrer, R. & Haass, C. Intramembrane proteolysis by gamma-secretase. J. Biol. Chem. 283, 29627–29631 (2008).
Gomez-Lamarca, M. J. et al. Activation of the notch signaling pathway in vivo elicits changes in CSL nuclear dynamics. Dev. Cell 44, 611–623 (2018). This study supports a dynamic model for CSL transcriptional activation by NICD.
Vilimas, T. et al. Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat. Med. 13, 70–77 (2007). Vilimas et al. (2007), Vacca et al. (2006), Song et al. (2008), Fernandez-Majada et al. (2007), Hossain et al. (Front. Oncol., 2018) and Hao et al. support the notion of IκB kinases as potentially druggable Notch signalling mediators in different malignancies.
Vacca, A. et al. Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia. EMBO J. 25, 1000–1008 (2006).
Song, L. L. et al. Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 27, 5833–5844 (2008).
Fernandez-Majada, V. et al. Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer. Proc. Natl Acad. Sci. USA 104, 276–281 (2007).
Hossain, F. et al. Notch signaling regulates mitochondrial metabolism and NF-kappaB activity in triple-negative breast cancer cells via IKKalpha-dependent non-canonical pathways. Front. Oncol. 8, 575 (2018).
Hao, L. et al. Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells. Oncogene 29, 201–213 (2010).
Shin, H. M. et al. NOTCH1 can initiate NF-kappaB activation via cytosolic interactions with components of the T cell signalosome. Front. Immunol. 5, 249 (2014).
Sade, H., Krishna, S. & Sarin, A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J. Biol. Chem 279, 2937–2944 (2004).
Landor, S. K. et al. Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms. Proc. Natl Acad. Sci. USA 108, 18814–18819 (2011).
Efferson, C. L. et al. Downregulation of Notch pathway by a gamma-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. Cancer Res. 70, 2476–2484 (2010).
Perumalsamy, L. R., Nagala, M. & Sarin, A. Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. Proc. Natl Acad. Sci. USA 107, 6882–6887 (2010). Perumalsamy et al. (2010) and Lee et al. (2013) describe mitochondrial Notch pathways in T cells and glioma stem cells, respectively.
Lee, K. S. et al. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev. 27, 2642–2647 (2013).
Xu, J. et al. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J. Clin. Invest. 125, 1579–1590 (2015).
Lee, S. F. et al. Gamma-secretase-regulated proteolysis of the Notch receptor by mitochondrial intermediate peptidase. J. Biol. Chem. 286, 27447–27453 (2011).
Pavlov, P. F. et al. Mitochondrial gamma-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein. FASEB J. 25, 78–88 (2011).
The authors wish to acknowledge the support of the U.S. National Cancer Institute (grant CA-P01-166009) and the Cancer Crusaders Foundation (L.M.).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
(EMT). A phenotypic switch, which can be reversible, whereby epithelial cancer cells acquire mesenchymal characteristics, including motility, and potentially stem-like characteristics.
- Cancer stem cells
(CSCs). Generally small populations of cells in malignancies that have stem-like characteristics: expression of embryonic or tissue stem cell markers, ability to divide symmetrically or asymmetrically, and resistance to chemotherapy and radiation.
A nucleoside resulting from the enzymatic hydrolysis of extracellular ATP by nucleoside triphosphate diphosphohydrolase 1 (also known as CD39), nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and ecto-5′ nucleotidase (also known as CD73).
- Myeloid-derived suppressor cells
(MDSCs). These include two main subtypes of immature myeloid cells (polymorphonuclear MDSCs and monocytic MDSCs), which are released from the bone marrow and migrate to the tumour microenvironment, where they suppress tumour immunity through a variety of mechanisms.
- Chimeric antigen receptor
(CAR). A recombinant transmembrane receptor designed to bind specific antigens and activate transduced patient T cells.
(Bispecific T cell engager). A recombinant bispecific antibody that uses one antigen-binding site to engage a tumour-selective antigen and an anti-CD3 antigen-binding site to non-specifically activate the T cell receptor of tumour-infiltrating lymphocytes.
About this article
Cite this article
Majumder, S., Crabtree, J.S., Golde, T.E. et al. Targeting Notch in oncology: the path forward. Nat Rev Drug Discov 20, 125–144 (2021). https://doi.org/10.1038/s41573-020-00091-3
This article is cited by
Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy
Molecular Biomedicine (2022)
Nature Biotechnology (2022)
Signal Transduction and Targeted Therapy (2022)
Comprehensive characterization of posttranscriptional impairment-related 3′-UTR mutations in 2413 whole genomes of cancer patients
npj Genomic Medicine (2022)
Molecular and Cellular Biochemistry (2022)