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.