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

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...

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Bibliographic Details
Published in:Cancer science 2021-11, Vol.112 (11), p.4711-4721
Main Authors: Kawamura, Yoshifumi, Saijo, Ken, Imai, Hiroo, Ishioka, Chikashi
Format: Article
Language:English
Subjects:
anaplastic thyroid carcinoma
angiogenesis
Antibodies
Antitumor activity
Cell cycle
CRISPR
Drug dosages
Growth factors
IL‐1
IRAK
IRAK protein
Kinases
lenvatinib
Medical prognosis
Mutation
Original
Patients
Phosphorylation
Proteins
Thyroid cancer
Tumors
Xenografts
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Summary: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. We screened for novel compounds that could enhance the antiproliferative effects of lenvatinib in anaplastic thyroid cancer (ATC), which is an extremely aggressive tumor with poor prognosis. We identified IRAK1/4 Inhibitor I as a candidate compound and examined its combined use with lenvatinib. In our HTC/C3 xenograft mouse model, tumor volume was significantly lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the control, IRAK1/4 Inhibitor I alone, and lenvatinib alone groups.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.15095