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Recent encouraging clinical activity of the geranylgeranyl transferase inhibitor GGTI\u20102418 (PTX\u2010100) in TCL prompted us to investigate HDACI interactions. HH, H9 and Hut78 TCL\u2010cell co\u2010treatment with the HDACIs belinostat or romidepsin with the GGTI\u20102418 methyl ester pro\u2010drug GGTI\u20102417 (GGTI) synergistically increased cell death. Synergism was mediated at least in part by AKT (Protein Kinase B)\u00a0inhibition as demonstrated by (a) the HDACI\/GGTI combination markedly decreased p\u2010AKT levels; (b) ectopic expression of constitutively active (myristoylated) AKT conferred significant resistance of cells to GGTI\/HDACI; (c) highly HDACI\u2010resistant HH and H9 cells expressed high basal levels of phosphorylated AKT that were downregulated by GGTI\/HDACI co\u2010administration, leading to cell death induction; (d) shRNA knockdown of AKT in HDACI\u2010resistant cells restored HDACI\/GGTI sensitivity. Finally, flank xenograft models revealed that HDACI\/GGTI combination treatment was significantly more effective than monotherapy in inhibiting in\u00a0vivo TCL tumour growth. These findings argue that combined GGTI\/HDACI exposure synergistically induces cell death and reduces HDACI resistance through an AKT\u2010dependent mechanism in TCL cells. In view of clinical results with GGTI\u20102418, the HDACI\/GGTI\u20102418 combination strategy warrants consideration in T\u2010cell malignancies.<\/jats:p>","DOI":"10.1111\/bjh.70188","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T03:55:01Z","timestamp":1759722901000},"page":"2368-2378","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Geranylgeranyl transferase\u20101 inhibitor\n                    <scp>GGTI<\/scp>\n                    \u20102417 enhances the anti\u2010tumour efficacy of histone deacetylase inhibitors in different T\u2010cell lymphoma lines"],"prefix":"10.1111","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8550-0896","authenticated-orcid":false,"given":"Xiaoyan","family":"Hu","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine Virginia Commonwealth University  Richmond Virginia 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