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.

Retinoids in the Pathogenesis and Treatment of Liver Diseases

“…For example, fenretinide induced apoptosis and showed anti-proliferative effects in HepG2, Huh 7, and HepB3 cells through RARβ actions [ 213 , 214 , 215 , 216 ]. Recently, researchers reported that sulfarotene (WYC-209), an acyclic retinoid, overcame HCC resistance in a subset of cancer cells that were responsible for drug resistance (i.e., tumor-repopulating cells), possibly via RARα [ 217 ]. A promising retinoid at present for the prevention of HCC recurrence is peretinoin (NIK-333) [ 218 , 219 ], which is in clinical trials that are discussed in a separate review [ 220 ].…”

Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma

“…S10 C), we found that clofazimine was more effective in cluster 1 and cluster 4, with flutamide and ATRA effective in cluster 4 and disulfiram effective in cluster 3. Notably, our previous study has identified that ATRA could not impact the proliferation and metastasis of HCC cell lines [ 18 ]. Therefore, we used clofazimine, disulfiram, and flutamide for further validation.…”

Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation

“…[ 43 ] By contrast, WYC‐209 shows a strong inhibition of solid tumor metastasis in vivo at very low concentrations. [ 11 , 44 ]…”

“…[43] By contrast, WYC-209 shows a strong inhibition of solid tumor metastasis in vivo at very low concentrations. [11,44] Over the last decade or so, a hypothesis that the extracellular matrix stiffens as a result of excessive collagen-1 is the underlying mechanism of cancer progression has been proposed. [45][46][47] A tacit implication of the model is that softening the extracellular matrix by inhibiting collagen-1 may be a strategy of treating cancer patients.…”