Modulation of Oncogenic NOTCH Signaling in Highly Aggressive Malignancies 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 review aims to assess γ-secretase inhibitors (GSIs) as anticancer agents in preclinical and clinical settings, focusing on their ability to block tumor progression, target cancer stem cells, and overcome resistance to standard 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. The review included preclinical in vitro and in vivo studies and clinical trials on GSIs as monotherapy or in combination with other therapies for TNBC, metastatic melanoma, PDAC, GC, and NSCLC. Excluded were duplicates, non-English articles, articles with unknown authors in Scopus, studies before 2010, studies on non-cancer conditions, studies unrelated to NOTCH signaling, and studies outside the cancer types under study. Risk of bias was assessed through study design factors like randomization, blinding, and data handling. Findings were synthesized qualitatively across the selected cancer types. Results. This review analyzes therapeutic advances using GSIs in cancers driven by oncogenic NOTCH signaling, based on 61 sources covering NSCLC, TNBC, metastatic melanoma, gastric cancer, PDAC, and global epidemiology data. Preclinical studies show GSIs synergize with chemotherapy, radiotherapy, and novel agents, especially in NSCLC, melanoma, and TNBC, blocking EMT, overcoming resistance, and improving prognosis. Common GSIs include DAPT and RO4929097, which enhance drugs like gemcitabine (PDAC), paclitaxel, osimertinib, erlotinib (NSCLC), and 5-FU (GC, TNBC). Promising combinations include GSIs with SAHA, ATRA, and CB103 in TNBC. Clinical trials remain limited: PDAC trials with gemcitabine showed no benefit; melanoma trials had modest results; TNBC trials showed partial responses but overall low efficacy and severe adverse events. RO4929097 is the most clinically tested GSI. Discussion. Clinical trials with γ-secretase inhibitors (GSIs) have underperformed despite promising preclinical results, largely due to tumor heterogeneity, dosing challenges, and non-selective inhibition. Future strategies should prioritize receptor-specific GSIs, patient stratification based on NOTCH pathway activation, and combination therapies administered at optimized doses. Emerging approaches include integrating immunotherapy with advanced techniques such as CRISPR, CAR-T cells, and bispecific antibodies, alongside targeted delivery systems to enhance efficacy and minimize toxicity. Addressing the tumor microenvironment, which contributes to therapy resistance, and inhibiting tumor angiogenesis are also active areas of investigation. Finally, leveraging artificial intelligence and big data for personalized medicine, including male- and female-specific considerations, will be critical for improving patient outcomes.