Notch signaling in cancer: metabolic reprogramming and therapeutic implications

Area of Science:

• Molecular Biology
• Developmental Biology
• Oncology

Background:

• The Notch signaling pathway is evolutionarily conserved and vital for cell-fate determination, organogenesis, and tissue homeostasis.
• Notch receptors and ligands, transmembrane proteins with epidermal growth factor-like repeats, initiate signaling upon binding.
• Notch signaling plays a dual role in cancer, acting as an oncogene or tumor suppressor depending on the context.

Purpose of the Study:

• To review the role of Notch signaling in cancer progression and therapeutic resistance.
• To discuss current clinical strategies targeting the Notch pathway.
• To identify future research priorities for effective Notch-targeted cancer therapies.

Main Methods:

• Literature review of Notch signaling in cancer.
• Analysis of current therapeutic approaches and their limitations.
• Discussion of emerging strategies and future directions.

Main Results:

• Aberrant Notch activation promotes epithelial-mesenchymal transition, cancer stem-like phenotypes, and metabolic reprogramming, contributing to tumor progression and therapeutic resistance.
• Current therapies include γ-secretase inhibitors (GSIs), antibodies, and synthetic Notch (synNotch) approaches.
• Clinical translation is hindered by dose-limiting toxicities, lack of predictive biomarkers, and pathway-compensatory resistance.

Conclusions:

• Future research should focus on developing selective Notch modulators and biomarker-guided combination therapies.
• Targeted delivery systems are needed to enhance the efficacy of Notch-targeted treatments.
• Realizing the full translational potential of Notch-targeted therapies requires addressing current clinical limitations in precision oncology.