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

Feng Qi,Junwei Chen,Yongde Luo,Yao Zhang,Wenxing Qin,Bing Niu,Jinglin Xia,Keqing Shi,Biwei Yang,Quanlin An,Zhijie Yu,Xin Cao

doi:10.1186/s13046-021-02085-4

Abstract

BackgroundRecurrent 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.MethodsSuppression 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).ResultsSulfarotene 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.ConclusionsOur 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.

Highlights

Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumorrepopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance
Transwell assays revealed significantly increased survival and migration of these TRCs over their parental cancer cells in vitro (Figure S2c). All inoculums of both types of TRCs, sampled at 5 × 105 cells selected from initial parental cancer cells, formed significant subcutaneous xenograft tumor nodes in BALB/c nude mice compared to none of their parental cancer cells at 30 days (Figure S2d, e), confirming the notable selfrenewal and tumorigenic properties of the isolated TRCs
After treatment for 5 days, we found that the colony spheroids from HCC TRCs were markedly suppressed by sulfarotene at concentrations ranging from 1.0 to 10 μM, compared to 10 μM for ACR or sorafenib (Fig. 1a)

Summary

Introduction

Recurrent hepatocellular carcinoma (HCC) shows strong resistance to sorafenib, and the tumorrepopulating cells (TRCs) with cancer stem cell-like properties are considered a driver for its high recurrent rate and drug resistance. Instead of the complex approaches used for the identification and isolation of CSCs or TICs, e.g. by sets of stem cell surface markers [5], that hamper study applicability, we adapted and developed a simple mechanical approach to select cancer stem-like cells while they were cultured in threedimensional (3D) soft fibrin gels [6] rather than twodimensional (2D) rigid dishes. Such selectively survived cancer stem-like cells were shown to be highly tumorigenic, and were defined as tumor-repopulating cells (TRCs) [6, 7]. The results suggested that the combination of sulfarotene with the efficient TRC selection for cancer stemlike cells could be used to better tackle the current HCC problems as aforementioned

Methods

Results

Discussion

Conclusion