Total for the last 12 months
number of access : ?
number of downloads : ?
ID 116609
Author
Wang, Rong Kanazawa University|Southern Medical University
Yamada, Tadaaki Kanazawa University|Kyoto Prefectural University of Medicine
Kita, Kenji Kanazawa University
Taniguchi, Hirokazu Kanazawa University|Nagasaki University
Arai, Sachiko Kanazawa University
Fukuda, Koji Kanazawa University
Terashima, Minoru Kanazawa University
Ishimura, Akihiko Kanazawa University
Nishiyama, Akihiro Kanazawa University
Tanimoto, Azusa Kanazawa University
Takeuchi, Shinji Kanazawa University
Ohtsubo, Koshiro Kanazawa University
Yamashita, Kaname Kanazawa University
Yamano, Tomoyoshi Kanazawa University
Yoshimura, Akihiro Kyoto Prefectural University of Medicine
Takayama, Koichi Kyoto Prefectural University of Medicine
Kaira, Kyoichi Saitama Medical University
Taniguchi, Yoshihiko National Hospital Organization Kinki-chuo Chest Medical Center
Atagi, Shinji National Hospital Organization Kinki-chuo Chest Medical Center
Hanayama, Rikinari Kanazawa University
Matsumoto, Isao Kanazawa University
Han, Xujun Kanazawa University
Matsumoto, Kunio Kanazawa University
Wang, Wei Southern Medical University
Suzuki, Takeshi Kanazawa University
Yano, Seiji Kanazawa University
Content Type
Journal Article
Description
Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.
Journal Title
Nature Communications
ISSN
20411723
NCID
AA12645905
Publisher
Springer Nature
Volume
11
Start Page
4607
Published Date
2020-09-14
Rights
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
University Hospital