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

Background. NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand binding, a cascade of proteolytic cleavages mediated by ADAM proteases and the γ-secretase complex activates the receptor, culminating in the release of the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it modulates gene expression. The main objective of this review is to analyze γ-secretase inhibitors (GSIs) as promising anticancer agents in preclinical studies and clinical trials, focusing on their ability to disrupt tumor progression, cancer stem cell maintenance, and resistance to conventional therapies.Methods. A systematic search was conducted in the ISI Web of Science, PubMed, and Scopus databases, following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Inclusion criteria required articles to be preclinical studies conducted in vitro or in vivo using mice or other animal models, or clinical trials in humans investigating GSIs either as monotherapy or in combination with other antitumor drugs targeting TNBC, metastatic melanoma, PDAC, GC, and NSCLC. Exclusion criteria included duplicate publications, articles not originally written in English, and studies focusing on GSIs in non-cancer pathologies such as Alzheimer’s disease. Studies investigating alternative therapeutic targets within the NOTCH signaling pathway that did not directly involve GSIs were also excluded. Risk of bias was assessed by evaluating study methodology, including randomization, blinding, handling of missing data, and other factors that could affect validity. Research synthesis was qualitative, summarizing and comparing the findings of the included studies.Results. We evaluated the main therapeutic advances achieved through GSIs in vitro, in vivo, and in clinical trials across cancers where NOTCH signaling is oncogenic. The dataset included 10 articles on NSCLC, 17 on breast cancer and TNBC, 14 on metastatic melanoma, 13 on GC, 10 on PDAC, 20 on general aspects of NOTCH signaling and therapeutic strategies in cancer, and 2 web pages on global cancer epidemiology. Although GSIs have entered clinical trials for PDAC, metastatic melanoma, and TNBC, their efficacy remains limited. However, combinatorial strategies involving GSIs, ADAM secretase inhibitors, and other antitumor agents have shown promise in improving treatment outcomes and reducing side effects.Discussion. Despite encouraging preclinical findings across multiple cancer types, clinical trials have not yet yielded the expected results, with the exception of TNBC. Future research should aim to identify the specific NOTCH receptor(s) involved in each tumor type and tailor therapies, accordingly, considering gender-based prevalence differences. Additionally, nanoparticle-based delivery systems and synergistic drug combinations may enhance the therapeutic index of GSIs and ADAM inhibitors while minimizing adverse effects.