{"doi":"10.1111/bjh.70188","title":"Geranylgeranyl transferase‐1 inhibitor <scp>GGTI</scp> ‐2417 enhances the anti‐tumour efficacy of histone deacetylase inhibitors in different T‐cell lymphoma lines","abstract":"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.","journal":"British Journal of Haematology","year":2025,"id":547450,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9439,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1439847,"name":"Lin Li","orcid":"0000-0003-3178-1850","position":1,"is_corresponding":false},{"id":970974,"name":"Jewel Nkwocha","orcid":"0000-0002-8680-8793","position":2,"is_corresponding":false},{"id":1266066,"name":"Hitesh Vasiyani","orcid":"0009-0005-3767-6893","position":3,"is_corresponding":false},{"id":688336,"name":"Aslamuzzaman Kazi","orcid":"0009-0005-7403-7468","position":4,"is_corresponding":false},{"id":412075,"name":"Saı̈d M. Sebti","orcid":"0000-0001-5163-1038","position":5,"is_corresponding":false},{"id":736161,"name":"Steven Grant","orcid":"0000-0003-4452-9320","position":6,"is_corresponding":false},{"id":1007004,"name":"Xiaoyan Hu","orcid":"0000-0001-8550-0896","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:53:41.314800Z","pmid":"41047494","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}