| 描述信息 |
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance remains a key challenge in lung adenocarcinoma (LUAD) therapy. Here, to identify the key regulators of EGFR-TKI sensitivity or resistance, we constructed EGFR-TKI-sensitive and -resistant LUAD patient-derived xenografts (PDXs), and analyzed gene mutation changes among them. Using this strategy, we found an increased frequency of L12_16 amino acid deletion mutation in the signaling peptide region of NOTCH4 (NOTCH4ΔL12_16) among EGFR-TKI-sensitive PDXs in comparison to these in EGFR-TKI-resistant PDXs. A similar pattern of increased NOTCH4ΔL12_16 was also observed in EGFR-TKI-sensitive compared to those in EGFR-TKI-resistant LUAD patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI-resistant LUAD cells sensitized them to EGFR-TKIs, and this process is mainly mediated by the reduction of intracellular domain fragment of NOTCH4 (NICD4) caused by the disruption of NOTCH4 translocation from cytosol to plasma membrane due to NOTCH4ΔL12_16 mutation. Mechanistically, NICD4 competitively binds to the promoter region of HES1 gene over p-STAT3, and its reduction enhances the inhibitory regulation of EGFR-TKI-induced p-STAT3 on HES1 signaling. Furthermore, EGFR-TKI resistance could be reversed by inhibiting NOTCH4-HES1 signaling pathway using both inhibitors and siRNAs, suggesting that targeting NOTCH4-HES1 could be a novel strategy for overcoming EGFR-TKI resistance in LUAD. Altogether, we report for the first time that NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs in transcriptional regulation of HES1 and that targeted blockade of this signaling cohort can reverse EGFR-TKI resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI therapy. |
