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ID 114785
Arasada, Rajeswara Rao The Ohio State University
Shilo, Konstantin The Ohio State University
Yamada, Tadaaki Kanazawa University
Zhang, Jianying The Ohio State University
Yano, Seiji Kanazawa University
Ghanem, Rashelle The Ohio State University
Wang, Walter The Ohio State University
Takeuchi, Shinji Kanazawa University
Fukuda, Koji Kanazawa University
Katakami, Nobuyuki Institute of Biomedical Research and Innovation
Tomii, Keisuke Kobe City Medical Center General Hospital
Ogushi, Fumitaka National Hospital Organization National Kochi Hospital
Talabere, Tiffany The Ohio State University
Misra, Shrilekha The Ohio State University
Duan, Wenrui The Ohio State University
Fadda, Paolo The Ohio State University
Rahman, Mohammad A. The Ohio State University
Nana-Sinkam, Patrick The Ohio State University
Evans, Jason The Ohio State University
Amann, Joseph The Ohio State University
Tchekneva, Elena E. The Ohio State University
Dikov, Mikhail M. The Ohio State University
Carbone, David P. The Ohio State University
Content Type
Journal Article
EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
Journal Title
Nature Communications
Springer Nature
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© The Author(s) 2018
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Medical Sciences