NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1

Abstract

Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4ΔL12_16) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy.

Large-Scale Whole-Exome Sequencing Association Study Implicates Genetic Effects on Viral Oncogenesis and Tumor Microenvironment in Nasopharyngeal Carcinoma

“…These findings highlight the multifaceted cellular implications of germline variations in cancer susceptibility, resonating with a growing literature suggesting the engagement of various cell types in the development of complex disease 56–58 . Given that the validation of the functional relevance of genetic susceptibility genes often predominantly emphasizes the cells of cancer origin (e.g., epithelial cells in NPC), our findings call attention to the importance of exploring the roles of cancer risk genes across diverse TME cell types in cancer development (such as endothelial cells) 54,55 .…”

“…Such patterns are also observed in other cancers. For instance, the well-known susceptibility-associated genes NOTCH4 in lung cancer and SMAD1 in colorectal cancer 54,55 are exclusively expressed in endothelial cells (not typically developing into malignancy) in tumors. These findings highlight the multifaceted cellular implications of germline variations in cancer susceptibility, resonating with a growing literature suggesting the engagement of various cell types in the development of complex disease 56–58 .…”