2. Academic Validation
  3. Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846

Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846

  • Br J Cancer. 2021 Jan;124(1):228-236. doi: 10.1038/s41416-020-01162-3.
Teppei Sugano 1 2,  Mari Masuda 1,  Fumitaka Takeshita 3,  Noriko Motoi 4,  Toru Hirozane 5,  Naoko Goto 1,  Shigeki Kashimoto 6,  Yuko Uno 6,  Hideki Moriyama 6,  Masaaki Sawa 6,  Yuichi Nagakawa 7,  Akihiko Tsuchida 7,  Masahiro Seike 2,  Akihiko Gemma 2,  Tesshi Yamada 8 9
Affiliations

Affiliations

  • 1 Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
  • 2 Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, 113-8602, Japan.
  • 3 Department of Functional Analysis, Fundamental Innovative Oncology Core Center (FIOC), National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
  • 4 Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.
  • 5 Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
  • 6 Carna Biosciences, Inc, Kobe, 650-0047, Japan.
  • 7 Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, 160-0023, Japan.
  • 8 Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan. tesshi.yamada@gmail.com.
  • 9 Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, 160-0023, Japan. tesshi.yamada@gmail.com.
PMID: 33244122 DOI: 10.1038/s41416-020-01162-3
Abstract

Background: Metastasis is the primary cause of death in Cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of Cancer metastasis, and its pharmacological interference holds therapeutic promise.

Methods: Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFβ1-induced EMT of lung Cancer cells.

Results: NCB-0846 inhibited the TGFβ1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFβ1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFβ receptor type-I (TGFBR1) gene, at least partly through the induction of MicroRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186].

Conclusions: NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung Cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung Cancer patients.

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