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; David P Carbone

doi:10.1038/s41467-018-05626-2

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

Nat Commun. 2018 Aug 10;9(1):3198. doi: 10.1038/s41467-018-05626-2.

Authors

Rajeswara Rao Arasada¹, Konstantin Shilo², Tadaaki Yamada³, Jianying Zhang⁴, Seiji Yano³, Rashelle Ghanem⁵, Walter Wang⁵, Shinji Takeuchi³, Koji Fukuda³, Nobuyuki Katakami⁶, Keisuke Tomii⁷, Fumitaka Ogushi⁸, Yasuhiko Nishioka⁹, Tiffany Talabere⁵, Shrilekha Misra¹⁰, Wenrui Duan⁵, Paolo Fadda⁵, Mohammad A Rahman¹¹, Patrick Nana-Sinkam¹¹, Jason Evans⁵, Joseph Amann⁵, Elena E Tchekneva⁵, Mikhail M Dikov⁵, David P Carbone¹²

Affiliations

¹ Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, 43210, USA. [email protected].
² Department of Pathology, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
³ Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, 920-0934, Japan.
⁴ Center for Biostatistics, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
⁵ Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
⁶ Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, 650-0047, Japan.
⁷ Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, 650-0047, Japan.
⁸ Division of Pulmonary Medicine, National Hospital Organization National Kochi Hospital, Kochi, 780-8077, Japan.
⁹ Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan.
¹⁰ Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
¹¹ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine and the Center for Critical Care Medicine, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
¹² Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, 43210, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Carcinoma, Non-Small-Cell Lung / blood
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
DNA-Binding Proteins / metabolism
Drug Resistance, Neoplasm / drug effects
Epithelial-Mesenchymal Transition / drug effects
ErbB Receptors / genetics
Humans
Lung Neoplasms / blood
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Mice, Inbred NOD
Mice, SCID
Mutation / genetics*
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Phenotype
Plasminogen Activator Inhibitor 1 / blood
Protein Kinase Inhibitors / pharmacology*
Protein Stability / drug effects
Receptor, Notch3 / metabolism*
Signal Transduction*
Transcription Factors / metabolism
beta Catenin / antagonists & inhibitors
beta Catenin / metabolism*

Substances

DNA-Binding Proteins
MAML1 protein, human
NOTCH3 protein, human
Plasminogen Activator Inhibitor 1
Protein Kinase Inhibitors
Receptor, Notch3
Transcription Factors
beta Catenin
EGFR protein, human
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding