The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model

J Exp Clin Cancer Res. 2018 Sep 21;37(1):234. doi: 10.1186/s13046-018-0907-z.

Abstract

Background: The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential amino acids across the plasma membrane. While LAT1 is overexpressed in a variety of human neoplasms, its expression and its role in thyroid cancer is currently unknown. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy for which no effective therapy exists. The purpose of this study was to explore whether the inhibition of LAT1 in ATC would affect tumor growth both in vitro and in vivo.

Methods: LAT1 was pharmacologically blocked by JPH203 in human ATC and papillary thyroid cancer (PTC) cell lines. The effects on proliferation and mTORC1 activity were addressed in vitro. A genetically engineered mouse model of ATC was used to address the effect of blocking LAT1 on tumor growth in vivo. SLC7A5 transcription was measured in patient-derived ATC samples to address the clinical relevance of the findings.

Results: LAT1 block by JPH203 reduced proliferation and mTORC1 signaling in human thyroid cancer cell lines. SLC7A5 transcription was upregulated in ATC tissues derived from a genetically engineered mouse model and in ATC samples recovered from patients. JPH203 treatment induced thyroid tumor growth arrest in vivo in a fully immunocompetent mouse model of thyroid cancer. Additionally, analysis of publicly available datasets of thyroid carcinomas revealed that high LAT1 expression is associated with potentially untreatable PTC presenting reduced NIS/SLC5A5 transcription and with ATC.

Conclusions: These preclinical results show that LAT1 inhibition is a novel therapeutic approach in the context of thyroid cancers, and more interestingly in untreatable thyroid cancers.

Keywords: ATC; BRAF; Genetically engineered mice; SLC7A5; mTOR.

MeSH terms

  • Animals
  • Animals, Genetically Modified / genetics
  • Apoptosis / drug effects
  • Benzoxazoles / administration & dosage
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Large Neutral Amino Acid-Transporter 1 / drug effects
  • Large Neutral Amino Acid-Transporter 1 / genetics*
  • Mice
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Signal Transduction / drug effects
  • Thyroid Carcinoma, Anaplastic / drug therapy*
  • Thyroid Carcinoma, Anaplastic / genetics
  • Thyroid Carcinoma, Anaplastic / pathology
  • Thyroid Gland / drug effects
  • Thyroid Gland / pathology
  • Tyrosine / administration & dosage
  • Tyrosine / analogs & derivatives

Substances

  • 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid
  • Benzoxazoles
  • Large Neutral Amino Acid-Transporter 1
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • Pik3ca protein, mouse
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf