Inhibition of IRAK1/4 enhances the antitumor effect of lenvatinib in anaplastic thyroid cancer cells

Cancer Sci. 2021 Nov;112(11):4711-4721. doi: 10.1111/cas.15095. Epub 2021 Sep 15.


Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor associated with poor prognosis due to a lack of efficient therapies. In Japan, lenvatinib is the only drug approved for patients with ATC; however, its efficacy is limited. Therefore, novel therapeutic strategies are urgently required for patients with ATC. The present study aimed to identify compounds that enhance the antiproliferative effects of lenvatinib in ATC cells using a compound library. IRAK1/4 Inhibitor I was identified as a candidate compound. Combined treatment with lenvatinib and IRAK1/4 Inhibitor I showed synergistic antiproliferative effects via the induction of cell cycle arrest at G2/M phase in the ATC cell lines 8305C, HTC/C3, ACT-1, and 8505C. Furthermore, IRAK1/4 Inhibitor I enhanced the inhibition of ERK phosphorylation by lenvatinib in 8305C, HTC/C3, and 8505C cells. In an HTC/C3 xenograft mouse model, tumor volume was lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the vehicle control, IRAK1/4 Inhibitor I, and lenvatinib groups. IRAK1/4 Inhibitor I was identified as a promising compound that enhances the antiproliferative and antitumor effects of lenvatinib in ATC.

Keywords: IL-1; IRAK; anaplastic thyroid carcinoma; angiogenesis; lenvatinib.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Drug Synergism
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Gene Knockout Techniques
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • M Phase Cell Cycle Checkpoints / drug effects
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phenylurea Compounds / therapeutic use*
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use
  • Quinolines / therapeutic use*
  • Thyroid Carcinoma, Anaplastic / drug therapy*
  • Thyroid Neoplasms / drug therapy*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Quinolines
  • IRAK1 protein, human
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • lenvatinib