2. Academic Validation
  3. A novel small-molecule inhibitor of trefoil factor 3 (TFF3) potentiates MEK1/2 inhibition in lung adenocarcinoma

A novel small-molecule inhibitor of trefoil factor 3 (TFF3) potentiates MEK1/2 inhibition in lung adenocarcinoma

  • Oncogenesis. 2019 Nov 4;8(11):65. doi: 10.1038/s41389-019-0173-8.
Mengyi Zhang 1 2 3,  Baocheng Wang 4 5,  Qing-Yun Chong 3,  Vijay Pandey 5 6,  Zhirong Guo 7,  Ru-Mei Chen 2 3,  Lingzhi Wang 2 3,  Yanxin Wang 2 3,  Lan Ma 5,  Alan P Kumar 2 3 8,  Tao Zhu 9,  Zheng-Sheng Wu 10,  Zhinan Yin 4,  Basappa 11,  Boon-Cher Goh 2 3 12,  Peter E Lobie 13 14 15
Affiliations

Affiliations

  • 1 College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
  • 2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 3 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 4 Biomedical Translational Research Institute, Jinan University, Guangzhou, China.
  • 5 Tsinghua Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, China.
  • 6 Shenzhen Bay Laboratory, Shenzhen, Guangzhou, China.
  • 7 Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
  • 8 Cancer Program, Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 9 Department of Oncology of the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
  • 10 Department of Pathology, Anhui Medical University, Hefei, Anhui, China.
  • 11 Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India.
  • 12 Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
  • 13 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. pelobie@sz.tsinghua.edu.cn.
  • 14 Tsinghua Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, China. pelobie@sz.tsinghua.edu.cn.
  • 15 Shenzhen Bay Laboratory, Shenzhen, Guangzhou, China. pelobie@sz.tsinghua.edu.cn.
PMID: 31685806 DOI: 10.1038/s41389-019-0173-8
Abstract

TFF3 has been identified as a novel biomarker to distinguish between lung adenocarcinoma (ADC) and lung squamous-cell carcinoma (SCC). Herein, we determined the oncogenic functions of TFF3 and demonstrated the potential of pharmacological inhibition of TFF3 in lung ADC using a novel small-molecule inhibitor of TFF3 dimerization (AMPC). Forced expression of TFF3 in lung ADC cells enhanced cell proliferation and survival, increased anchorage-independent growth, Cancer stem cell behavior, growth in 3D Matrigel, and cell migration and invasion. In contrast, depleted expression of TFF3 suppressed these cellular functions. Mechanistically, TFF3 exerted its oncogenic function through upregulation of ARAF and hence enhanced downstream activation of MEK1/2 and ERK1/2. Pharmacological inhibition of TFF3 by AMPC, resulted in markedly decreased cell survival, proliferation, 3D growth and foci formation, and impaired tumor growth in a xenograft mouse model. Moreover, the combination of various MEK1/2 inhibitors with AMPC exhibited synergistic inhibitory effects on lung ADC cell growth. In conclusion, this study provides the first evidence that TFF3 is a potent promoter of lung ADC progression. Targeting TFF3 with a novel small-molecule inhibitor alone or in combination with conventional MEK1/2 inhibitors are potential strategies to improve the outcome of lung ADC.

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