{"doi":"10.3390/cancers14010160","title":"PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma","abstract":"Diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma (FL), and mantle cell lymphoma (MCL) are aggressive non-Hodgkin's lymphomas (NHL). Cure rates are suboptimal and novel treatment strategies are needed to improve outcomes. Here, we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) is critical for lymphoma subsistence. Dual targeting of PAK4-NAMPT by the Phase I small molecule KPT-9274 suppressed cell proliferation in DLBCL, FL, and MCL. Growth inhibition was concurrent with apoptosis induction alongside activation of pro-apoptotic proteins and reduced pro-survival markers. We observed NAD suppression, ATP reduction, and consequent cellular metabolic collapse in lymphoma cells due to KPT-9274 treatment. KPT-9274 in combination with standard-of-care chemotherapeutics led to superior inhibition of cell proliferation. In vivo, KPT-9274 could markedly suppress the growth of WSU-DLCL2 (DLBCL), Z-138, and JeKo-1 (MCL) sub-cutaneous xenografts, and a remarkable increase in host life span was shown, with a 50% cure of a systemic WSU-FSCCL (FL) model. Residual tumor analysis confirmed a reduction in total and phosphorylated PAK4 and activation of the pro-apoptotic cascade. This study, using various preclinical experimental models, demonstrates the therapeutic potential of targeting PAK4-NAMPT in DLBCL, FL, and MCL. The orally bioavailable, safe, and efficacious PAK4-NAMPT dual inhibitor KPT-9274 warrants further clinical investigation.","journal":"Cancers","year":2021,"id":178985,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402158,"name":"Md. Hafiz Uddin","orcid":"0000-0002-0188-6857","position":1,"is_corresponding":false},{"id":655023,"name":"Suresh Kumar Balasubramanian","orcid":"0000-0001-9044-1309","position":2,"is_corresponding":false},{"id":725636,"name":"Noor A. Sulaiman","orcid":"0000-0001-8356-8758","position":3,"is_corresponding":false},{"id":725637,"name":"Marium Iqbal","orcid":"0000-0002-2374-7559","position":4,"is_corresponding":false},{"id":709375,"name":"Mahmoud Chaker","orcid":null,"position":5,"is_corresponding":false},{"id":470519,"name":"Amro Aboukameel","orcid":null,"position":6,"is_corresponding":false},{"id":696563,"name":"Yiwei Li","orcid":"0000-0003-2389-3203","position":7,"is_corresponding":false},{"id":308467,"name":"William Senapedis","orcid":"0009-0004-1566-2733","position":8,"is_corresponding":false},{"id":73842,"name":"Erkan Baloglu","orcid":"0000-0002-4106-732X","position":9,"is_corresponding":false},{"id":469427,"name":"Ramzi M. Mohammad","orcid":"0000-0001-8332-5246","position":10,"is_corresponding":false},{"id":268265,"name":"Jeffrey A. Zonder","orcid":"0000-0002-1741-2795","position":11,"is_corresponding":false},{"id":469428,"name":"Asfar S. Azmi","orcid":"0000-0003-1178-9505","position":12,"is_corresponding":false},{"id":469418,"name":"Husain Yar Khan","orcid":"0000-0002-9161-1514","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:47:44.875897Z","pmid":"35008323","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":[]}