Geranylgeranyl transferase-1 inhibitor GGTI-2417 enhances the anti-tumour efficacy of histone deacetylase inhibitors in different T-cell lymphoma lines.

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.