Characterization of selinexor response/resistance in hepatocellular carcinoma

Background and Aims The nuclear transport system is intrinsically linked to tumor-relevant signaling cascades and selective inhibitors of nuclear export represent a promising approach for cancer treatment. The exportin-1 (XPO-1) inhibitor selinexor is already approved for treating hematological neoplasms, whereas its efficacy in solid tumors including liver cancer is poorly understood. In this study we aim to identify candidates potentially involved in selinexor response/resistance.

Method A variety of human (HepG2, Hep3B, HLE and HLF) liver cancer lines were treated with selinexor under several conditions. The cells were then analyzed via qPCR, MTT viability assays and LC-MS/MS-based proteomics. Potential response- or resistance-related candidates were further investigated via silencing (siRNA) or overexpression (cDNA) in vitro.

Results HepG2 and Hep3B responded well to selinexor treatment (0.25 µM, 72 h) showing a residual viability of 25%, whereas HLE and HLF remained largely unaffected. Proteomic analyses revealed significantly higher abundance of Glutathione S-transferase P (GSTP1), Myoferlin (MYOF) and Profilin-1 (PFN1) among others in the selinexor-treated non-responding group. These candidates were previously linked to exosome formation and cytoskeleton remodeling as well as drug resistance. Furthermore, we detected a dose-dependent increase of programmed death ligand 1 (PD-L1) mRNA expression (up to ~11-fold) upon selinexor treatment.

Conclusion Our data suggest that selinexor resistance in HCC is related to proteins involved in exosome formation and cytoskeleton remodeling. In addition, selinexor directly or indirectly affects PD-L1 expression in liver cancer with potential relevance for (combined) immune checkpoint therapy.

Publication History

Article published online:
23 January 2024