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

Takahashi, Hirofumi; Sakakibara-Konishi, Jun; Furuta, Megumi; Shoji, Tetsuaki; Tsuji, Kosuke; Morinaga, Daisuke; Kikuchi, Eiki; Kikuchi, Junko; Noguchi, Takuro; Hatanaka, Kanako C.; Hatanaka, Yutaka; Shinagawa, Naofumi; Konno, Satoshi

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

Takahashi, Hirofumi; Sakakibara-Konishi, Jun; Furuta, Megumi et al.

Cancer science, 2023, 114(4), 1635-1650

Permalink : https://hdl.handle.net/2115/88918

このアイテムのアクセス数:311件（2026-08-13 19:01 集計）

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https://doi.org/10.1111/cas.15674			82

論文情報

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アクセス権	open access
URI	https://hdl.handle.net/2115/88918
タイトル	Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer
著者	Takahashi, Hirofumi ; Sakakibara-Konishi, Jun ; Furuta, Megumi ; Shoji, Tetsuaki ; Tsuji, Kosuke ; Morinaga, Daisuke ; Kikuchi, Eiki ; Kikuchi, Junko ; Noguchi, Takuro ; Hatanaka, Kanako C. ; Hatanaka, Yutaka ; Shinagawa, Naofumi ; Konno, Satoshi
著者名 Takahashi, Hirofumi
e-Rad_Researcher 50374278 著者名 Sakakibara-Konishi, Jun
著者名 Furuta, Megumi
著者名 Shoji, Tetsuaki
著者名 Tsuji, Kosuke
著者名 Morinaga, Daisuke
著者名 Kikuchi, Eiki
著者名 Kikuchi, Junko
著者名 Noguchi, Takuro
著者名 Hatanaka, Kanako C.
著者名 Hatanaka, Yutaka
著者名 Shinagawa, Naofumi
e-Rad_Researcher 20399835 著者名 Konno, Satoshi
言語	英語
キーワード	drug-tolerant persister cell
	epidermal growth factor receptor-tyrosine kinase inhibitor
	non-small-cell lung cancer
	Notch
	gamma-secretase inhibitor
発行日	2023-04
出版者	John Wiley & Sons
収録物名	Cancer science
巻(号)	114(4)
ページ	1635-1650
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
PISSN	1347-9032
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1111/cas.15674