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Several classes of Notch inhibitors have been developed, including monoclonal antibodies against NOTCH receptors or ligands, decoys, blocking peptides, and \u03b3-secretase inhibitors (GSIs). GSIs block a critical proteolytic step in NOTCH activation and are the most widely studied. Current treatments with GSIs have not successfully passed clinical trials because of side effects that limit the maximum tolerable dose. Multiple \u03b3-secretase\u2013cleavage substrates may be involved in carcinogenesis, indicating that there may be other targets for GSIs. Resistance mechanisms may include PTEN inactivation, mutations involving FBXW7, or constitutive MYC expression conferring independence from NOTCH1 inactivation. Recent studies have suggested that selective targeting \u03b3-secretase may offer an improved efficacy and toxicity profile over the effects caused by broad-spectrum GSIs. Understanding the mechanism of GSI-induced cell death and the ability to accurately identify patients based on the activity of the pathway will improve the response to GSI and support further investigation of such compounds for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Implications for Practice<\/jats:title>\n                  <jats:p>\u03b3-secretase has been proposed as a therapeutic target in numerous human conditions, including cancer. A better understanding of the structure and function of the \u03b3-secretase inhibitor (GSI) would help to develop safe and effective \u03b3-secretase\u2013based therapies. The ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. Toward these ends, this study focused on \u03b3-secretase inhibitors as a potential therapeutic target for the design of anti-NOTCH1 therapies for the treatment of T-cell acute lymphoblastic leukemias and lymphomas.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/onco.13595","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T05:15:35Z","timestamp":1605503735000},"page":"e298-e305","source":"Crossref","is-referenced-by-count":28,"title":["More Insights on the Use of \u03b3-Secretase Inhibitors in Cancer Treatment"],"prefix":"10.1093","volume":"26","author":[{"given":"Pilar","family":"L\u00f3pez-Nieva","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid (CSIC-UAM), Madrid, Spain"},{"name":"IIS Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Madrid, Spain"},{"name":"Consorcio de Investigaci\u00f3n Biom\u00e9dica de 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