Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway.

Abstract

BACKGROUND:

Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumor-repopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance.

METHODS:

Suppression of TRCs may thus be an effective therapeutic strategy for treating this fatal disease. We evaluated the pharmacology and mechanism of sulfarotene, a new type of synthetic retinoid, on the cancer stem cell-like properties of HCC TRCs, and assessed its preclinical efficacy in models of HCC patient-derived xenografts (PDXs).

RESULTS:

Sulfarotene selectively inhibited the growth of HCC TRCs in vitro and significantly deterred TRC-mediated tumor formation and lung metastasis in vivo without apparent toxicity, with an IC50 superior to that of acyclic retinoid and sorafenib, to which the recurrent HCC exhibits significant resistance at advanced stage. Sulfarotene promoted the expression and activation of RARα, which down-regulated SOS2, a key signal mediator associated with RAS activation and signal transduction involved in multiple downstream pathways. Moreover, sulfarotene selectively inhibited tumorigenesis of HCC PDXs with high expression for SOS2.

CONCLUSIONS:

Our study identified sulfarotene as a selective inhibitor for the TRCs of HCC, which targets a novel RARα-SOS2-RAS signal nexus, shedding light on a new, promising strategy of target therapy for advanced liver cancer.

• Authors: Feng Qi, Wenxing Qin, Yao Zhang, Yongde Luo, Bing Niu, Quanlin An, Biwei Yang, Keqing Shi, Zhijie Yu, Junwei Chen, Xin Cao, Jinglin Xia
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 280 (Sep 04 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34479623 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Retinoids
• Son of Sevenless Proteins
• Sos2 protein, mouse
• Sorafenib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Mice
• Retinoids (pharmacology, therapeutic use)
• Signal Transduction
• Son of Sevenless Proteins (drug effects)
• Sorafenib (pharmacology, therapeutic use)