Summary:Histone deacetylase inhibitors (HDACIs) are approved for T‐cell lymphoma (TCL) treatment, but resistance represents a major problem. Recent encouraging clinical activity of the geranylgeranyl transferase inhibitor GGTI‐2418 (PTX‐100) in TCL prompted us to investigate HDACI interactions. HH, H9 and Hut78 TCL‐cell co‐treatment with the HDACIs belinostat or romidepsin with the GGTI‐2418 methyl ester pro‐drug GGTI‐2417 (GGTI) synergistically increased cell death. Synergism was mediated at least in part by AKT (Protein Kinase B) inhibition as demonstrated by (a) the HDACI/GGTI combination markedly decreased p‐AKT levels; (b) ectopic expression of constitutively active (myristoylated) AKT conferred significant resistance of cells to GGTI/HDACI; (c) highly HDACI‐resistant HH and H9 cells expressed high basal levels of phosphorylated AKT that were downregulated by GGTI/HDACI co‐administration, leading to cell death induction; (d) shRNA knockdown of AKT in HDACI‐resistant cells restored HDACI/GGTI sensitivity. Finally, flank xenograft models revealed that HDACI/GGTI combination treatment was significantly more effective than monotherapy in inhibiting in vivo TCL tumour growth. These findings argue that combined GGTI/HDACI exposure synergistically induces cell death and reduces HDACI resistance through an AKT‐dependent mechanism in TCL cells. In view of clinical results with GGTI‐2418, the HDACI/GGTI‐2418 combination strategy warrants consideration in T‐cell malignancies.
