Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

Rajeswara Rao Arasada (), Konstantin Shilo, Tadaaki Yamada, Jianying Zhang, Seiji Yano, Rashelle Ghanem, Walter Wang, Shinji Takeuchi, Koji Fukuda, Nobuyuki Katakami, Keisuke Tomii, Fumitaka Ogushi, Yasuhiko Nishioka, Tiffany Talabere, Shrilekha Misra, Wenrui Duan, Paolo Fadda, Mohammad A. Rahman, Patrick Nana-Sinkam, Jason Evans, Joseph Amann, Elena E. Tchekneva, Mikhail M. Dikov and David P. Carbone ()
Additional contact information
Rajeswara Rao Arasada: The Ohio State University Medical Center
Konstantin Shilo: The Ohio State University Medical Center
Tadaaki Yamada: Kanazawa University Cancer Research Institute
Jianying Zhang: The Ohio State University Medical Center
Seiji Yano: Kanazawa University Cancer Research Institute
Rashelle Ghanem: The Ohio State University Medical Center
Walter Wang: The Ohio State University Medical Center
Shinji Takeuchi: Kanazawa University Cancer Research Institute
Koji Fukuda: Kanazawa University Cancer Research Institute
Nobuyuki Katakami: Institute of Biomedical Research and Innovation
Keisuke Tomii: Kobe City Medical Center General Hospital
Fumitaka Ogushi: National Hospital Organization National Kochi Hospital
Yasuhiko Nishioka: Tokushima University
Tiffany Talabere: The Ohio State University Medical Center
Shrilekha Misra: The Ohio State University Medical Center
Wenrui Duan: The Ohio State University Medical Center
Paolo Fadda: The Ohio State University Medical Center
Mohammad A. Rahman: The Ohio State University Medical Center
Patrick Nana-Sinkam: The Ohio State University Medical Center
Jason Evans: The Ohio State University Medical Center
Joseph Amann: The Ohio State University Medical Center
Elena E. Tchekneva: The Ohio State University Medical Center
Mikhail M. Dikov: The Ohio State University Medical Center
David P. Carbone: The Ohio State University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05626-2

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