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
  • 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. [email protected].
  • 9. Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, 160-0023, Japan. [email protected].
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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