Abstract
Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Previous work has shown strong cell cycle effects and drug-induced cell death across many different cancer-derived cell lines. Here, we report strong cell cycle-associated DNA double-stranded break formation upon the treatment of cancer cells with SINE. In multiple cell models, selinexor treatment results in the formation of clustered DNA damage foci in 30-40% of cells within 8 hours that is dependent upon cysteine-528. DNA damage strongly correlates with G1/S-phase and decreased DNA replication. Live cell microscopy reveals an association between DNA damage and cell fate. Cells that form damage in G1-phase more often die or arrest, while those damaged in S/G2-phase frequently progress to cell division. Up to half of all treated cells form damage foci, and most cells that die after being damaged, were damaged in G1-phase. By comparison, non-transformed cell lines show strong cell cycle effects but little DNA damage and less death than cancer cells. Significant drug combination effects occur when selinexor is paired with different classes of agents that either cause DNA damage or that diminish DNA damage repair. These data present a novel effect of exportin-1 inhibition and provide a strong rationale for multiple combination treatments of selinexor with agents that are currently in use for the treatment of different solid cancers.
Highlights
Selective inhibitors of nuclear export (SINE) are a first-in-class family of compounds with potential clinical application in different disease states, including inflammation, autoimmunity, ALS and cancers [1,2,3,4,5,6]
DNA damage after SINE treatment depends on XPO1 Cysteine-528
Cell-based effects after XPO1 inhibition by SINE begin within hours of treatment, including the nuclear sequestration of cargos, cell cycle effects, and cell death [6, 10, 12]
Summary
Selective inhibitors of nuclear export (SINE) are a first-in-class family of compounds with potential clinical application in different disease states, including inflammation, autoimmunity, ALS and cancers [1,2,3,4,5,6]. Within hours of SINE treatment, cargo sequestration, cell cycle arrest and progression defects, and activation of apoptosis are observed [10, 13]. Flow cytometry experiments in several studies report G1-phase accumulation and a rapid loss of the S-phase population after inhibition of XPO1 [13]. It is unclear from these studies what the fates of the cells accumulating in G1/S-phase are: progression and division, arrest, or death. Cell stresses that may account for arrest and cell death in G1-phase and S-phase associated phenotypes –or– that in turn may be caused by abnormal S-phase progression, are unclear after selinexor treatment
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