HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation.
Int J Biol Sci
; 20(8): 3046-3060, 2024.
Article
in En
| MEDLINE
| ID: mdl-38904018
ABSTRACT
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenylurea Compounds
/
Quinolines
/
Carcinoma, Hepatocellular
/
Proto-Oncogene Proteins c-akt
/
Histone Deacetylase Inhibitors
/
Liver Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Int J Biol Sci
Journal subject:
BIOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China