{"doi":"10.1016/j.neo.2024.101014","title":"Aurkin-A, a TPX2-Aurora A small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma","abstract":"• Alisertib, an ATP site inhibitor of Aurora A kinase, induces cell cycle dysregulation and polyploidy in Diffuse Large B Cell Lymphoma. • The combination of alisertib and Aurkin A, an Aurora A TPX2 site inhibitor, prevents polyploidy and increases apoptosis. Chemotherapy induced polyploidy is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL). Propidium iodide flow cytometry was utilized to quantify alisertib induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after 5 days of treatment. Combination of Aurkin A an AK-A/TPX2 site inhibitor, plus alisertib disrupted alisertib induced polyploidy in a dose-dependent manner with associated increased apoptosis. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G 2 /M) and cdt1-mKO (G 1 ), to monitor cell cycle progression. Using this system, we identified alisertib induces polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL mouse xenograft model, we show polyploidy generation in alisertib treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy to vehicle control levels. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in DLBCL cells. Visual Abstract: Alisertib and Aurkin A inhibition of aurora A kinase. Image A depicts fully activated AK-A with ATP bound to the ATP binding site along with TPX2 bound to the allosteric binding site. Alisertib will bind to the ATP binding site preventing ATP binding and AK-A activation (B). Aurkin A will displace TPX2 (colored orange), preventing allosteric activation of AK-A.","journal":"Neoplasia","year":2024,"id":450307,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":856173,"name":"Bárbara de la Peña Avalos","orcid":"0000-0001-9796-8015","position":1,"is_corresponding":false},{"id":1270821,"name":"Jonathan Dao","orcid":null,"position":2,"is_corresponding":false},{"id":1270822,"name":"Sebastian Montagnino","orcid":null,"position":3,"is_corresponding":false},{"id":240059,"name":"Dmytro Kovalskyy","orcid":"0000-0002-1143-8724","position":4,"is_corresponding":false},{"id":252086,"name":"Eloïse Dray","orcid":"0000-0001-6793-9838","position":5,"is_corresponding":false},{"id":1050691,"name":"Daruka Mahadevan","orcid":"0000-0002-7129-5593","position":6,"is_corresponding":false},{"id":1270457,"name":"Patrick Conway","orcid":"0000-0003-2835-5834","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:02:25.004119Z","pmid":"38875929","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":[]}