Understanding the roles of NOTCH signaling in cancer resistance

Cancer remains a leading cause of death globally, with lung cancer being particularly lethal. Despite advancements in diagnostics and therapies, the five-year survival rates for advanced tumors have seen minimal improvement, largely due to therapeutic resistance. This resistance can be genetic or nongenetic, with the latter being less understood but increasingly recognized for its role in treatment failure.

Non-genetic resistance is associated with resistant cancer cells that have innate or acquired drug resistance traits. These cells are often found in heterogeneous tumors and include cancer stem-like cells (CSCs), cells undergoing epithelial-to-mesenchymal transition (EMT), partial EMT cells, and drug-tolerant persisters (DTPs). NOTCH signaling plays a crucial role in tumorigenesis and therapeutic resistance, with its activation linked to drug resistance in various cancers.

The NOTCH family includes four receptors (NOTCH1-4) and interacts with ligands like Delta-like (DLL) and Jagged (JAG). NOTCH signaling can be canonical or noncanonical. Canonical signaling involves the cleavage of NOTCH receptors and the subsequent activation of target genes through the NICD-RBPJ complex. Noncanonical signaling involves interactions with other pathways without RBPJ involvement.

The NOTCH pathway contributes to resistance by regulating cell survival, apoptosis, and the tumor microenvironment. For example, NOTCH1 upregulation in lung adenocarcinoma is associated with taxane resistance, and its inhibition can resensitize resistant cells to treatment. NOTCH signaling also promotes immunosuppressive environments, hindering immunotherapy efficacy.

Resistant cancer cells exhibit traits like drug efflux, enhanced DNA repair, protein homeostasis, and an immunosuppressive microenvironment. NOTCH signaling influences these traits through interactions with other pathways like TGF-β, WNT, and hypoxia signaling. The canonical NOTCH pathway maintains resistant cell populations, while the noncanonical pathway modulates their resistance traits.

Therapeutic strategies targeting NOTCH signaling include γ-secretase inhibitors (GSIs), monoclonal antibodies against NOTCH ligands, and inhibitors of downstream effectors. However, clinical trials have faced challenges due to toxicity and limited dosing windows. Alternative strategies include targeting hypoxic resistant cells, lowering NOTCH inhibitor doses to reverse resistance without eliminating resistant cells, and targeting downstream regulators of noncanonical NOTCH signaling.

In conclusion, understanding the roles of NOTCH signaling in cancer resistance is critical for developing effective therapies. Future research should focus on distinguishing canonical and noncanonical NOTCH functions and improving targeting specificity to overcome resistance and enhance treatment outcomes.