title: Inhibition of Hec1 as a novel approach for treatment of primary liver cancer.
abstract: OBJECTIVE
  Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer.
  
  
  METHODS
  In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target.
  
  
  RESULTS
  In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50) > 10 μM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression.
  
  
  CONCLUSIONS
  Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.
authors.affiliation: Taivex Therapeutics Corporation, 17th Floor, No. 3, Yuanqu Street, Nangang District, Taipei City, 115, Taiwan, ROC, lynnhuang.lh245@gmail.com.
authors.forename: Lynn Y L
authors.initials: LY
authors.lastname: Huang
authors.forename: Chia-chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Ying-Shuan
authors.initials: YS
authors.lastname: Lee
authors.forename: Jiann-Jyh
authors.initials: JJ
authors.lastname: Huang
authors.forename: Shih-Hsien
authors.initials: SH
authors.lastname: Chuang
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.forename: Kuo-Jang
authors.initials: KJ
authors.lastname: Kao
authors.forename: Gillian M G
authors.initials: GM
authors.lastname: Lau
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Tsai
authors.forename: Chia-wei
authors.initials: CW
authors.lastname: Liu
authors.forename: Her-Sheng
authors.initials: HS
authors.lastname: Lin
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.forename: Johnson Y N
authors.initials: JY
authors.lastname: Lau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003598:Cytoskeletal Proteins; D015972:Gene Expression Regulation, Neoplastic; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D000072379:NIMA-Related Kinases; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C120529:NDC80 protein, human; D009687:Nuclear Proteins; C000592509:TA I-95; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases