| 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 |
| Notch |
| 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 |
| URI: | http://hdl.handle.net/2115/88918 |
| 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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