A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1

Sci Rep. 2019 Oct 10;9(1):14616. doi: 10.1038/s41598-019-51144-6.


A novel therapeutic approach is urgently needed for patients with anaplastic thyroid cancer (ATC) due to its fatal and rapid progress. We recently reported that ATC highly expressed MYC protein and blocking of MYC through its selective inhibitor, JQ1, decreased ATC growth and improved survival in preclinical models. One of the important roles of MYC is regulation of L-neutral amino acid transporter 1 (LAT1) protein and inhibition of LAT1 would provide similar anti-tumor effect. We first identified that while the human ATC expresses LAT1 protein, it is little or not detected in non-cancerous thyroidal tissue, further supporting LAT1 as a good target. Then we evaluated the efficacy of JPH203, a LAT1 inhibitor, against ATC by using the in vitro cell-based studies and in vivo xenograft model bearing human ATC cells. JPH203 markedly inhibited proliferation of three ATC cell lines through suppression of mTOR signals and blocked cell cycle progression from the G0/G1 phase to the S phase. The tumor growth inhibition and decrease in size by JPH203 via inhibition of mTOR signaling and G0/G1 cell cycle associated proteins were further confirmed in xenograft models. These preclinical findings suggest that LAT1 inhibitors are strong candidates to control ATC, for which current treatment options are highly limited.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzoxazoles / pharmacokinetics*
  • Benzoxazoles / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Large Neutral Amino Acid-Transporter 1 / metabolism
  • Mice
  • Molecular Targeted Therapy / methods
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Thyroid Carcinoma, Anaplastic / drug therapy*
  • Thyroid Carcinoma, Anaplastic / pathology
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology
  • Tyrosine / analogs & derivatives*
  • Tyrosine / pharmacokinetics
  • Tyrosine / therapeutic use
  • Xenograft Model Antitumor Assays


  • 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid
  • Antineoplastic Agents
  • Benzoxazoles
  • Large Neutral Amino Acid-Transporter 1
  • SLC7A5 protein, human
  • Tyrosine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases