HES1 and neoplasm: Introducing the Notch4ΔL12_16 mutation can reverse drug resistance, possibly by inducing a reduction in the intracellular domain (NICD4), weakening its competitive binding with p-STAT3 to the Hes1 promoter, enhancing p-STAT3’s transcriptional repression of Hes1, and ultimately increasing tumor sensitivity to EGFR-TKI (85).