Modulation of Oncogenic NOTCH Signaling in Highly Aggressive Neoplasia by Targeting the G-Secretase Complex. A Systematic Review

Background: NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand bind-ing, a cascade of proteolytic cleavages mediated by ADAM proteases and -secretase com-plex activates the receptor, culminating in the release of the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it modulates gene expression. γ-secretase inhibitors (GSIs) and ADAM secretases inhibitors have emerged as promising anticancer agents, with preclinical studies demonstrating their potential to disrupt tumor progres-sion, cancer stem cell maintenance, and resistance to conventional therapies. Methods. A systematic search was made of the ISIWeb of Science (http://www.webofknowledge.com) for the relevant works published from 2015 to October 2025 in the scientific cancer field according to the Preferred Reporting Items for Systematic Review (PRISMA) guidelines and by using appropriated search terms and the exclu-sion/inclusion strategy. Results. We evaluated the therapeutic advances achieved through GSIs in highly aggres-sive cancers where NOTCH signaling is oncogenic: pancreatic ductal adenocarcinoma (PDAC), gastric adenocarcinoma (GC), non-small cell lung cancer (NSCLC), metastatic melanoma, and triple-negative breast cancer (TNBC). Although GSIs have entered clinical trials for PDAC, metastatic melanoma, and TNBC, their efficacy remains limited. Howev-er, combinatorial strategies involving GSIs, ADAM secretase inhibitors and other anti-tumor agents have shown promise in enhancing treatment outcomes and reducing side effects. Discussion and Conclusions. Future research should focus on identifying the specific NOTCH receptor(s) involved in each tumor type and tailoring therapies, including con-sideration of gender-based prevalence differences. Moreover, nanoparticle-based delivery systems and synergistic drug combinations may further improve the therapeutic index of GSIs and ADAM inhibitors while minimizing adverse effects.