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Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer

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Title: Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer
Authors: Takahashi, Hirofumi Browse this author
Sakakibara-Konishi, Jun Browse this author →KAKEN DB
Furuta, Megumi Browse this author
Shoji, Tetsuaki Browse this author
Tsuji, Kosuke Browse this author
Morinaga, Daisuke Browse this author
Kikuchi, Eiki Browse this author
Kikuchi, Junko Browse this author
Noguchi, Takuro Browse this author
Hatanaka, Kanako C. Browse this author
Hatanaka, Yutaka Browse this author
Shinagawa, Naofumi Browse this author
Konno, Satoshi Browse this author →KAKEN DB
Keywords: drug-tolerant persister cell
epidermal growth factor receptor-tyrosine kinase inhibitor
non-small-cell lung cancer
gamma-secretase inhibitor
Issue Date: Apr-2023
Publisher: John Wiley & Sons
Journal Title: Cancer science
Volume: 114
Issue: 4
Start Page: 1635
End Page: 1650
Publisher DOI: 10.1111/cas.15674
Abstract: Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous-generation EGFR-TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a gamma-secretase inhibitor (GSI), a Notch inhibitor, impairs drug-tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho-ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR-TKI treatment in half of human EGFR-mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR-mutated NSCLC.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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