2. Academic Validation
  3. Aurkin-A, a TPX2-Aurora A small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma

Aurkin-A, a TPX2-Aurora A small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma

  • Neoplasia. 2024 Sep:55:101014. doi: 10.1016/j.neo.2024.101014.
Patrick J Conway 1,  Bárbara De La Peña Avalos 2,  Jonathan Dao 3,  Sebastian Montagnino 4,  Dmytro Kovalskyy 2,  Eloise Dray 5,  Daruka Mahadevan 6
Affiliations

Affiliations

  • 1 Department of Molecular Immunology & Microbiology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, USA; Department of Biomedical Sciences, Keiser University, 2600 N Military Trl, West Palm Beach, Florida, USA.
  • 2 Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, 8403 Floyd Curl Dr, San Antonio, Texas, USA.
  • 3 Long School of Medicine, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, USA.
  • 4 Department of Molecular Immunology & Microbiology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, USA.
  • 5 Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, 8403 Floyd Curl Dr, San Antonio, Texas, USA; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, USA. Electronic address: dray@uthscsa.edu.
  • 6 Mays Cancer Center, University of Texas Health Science Center San Antonio, 7979 Wurzbach Rd, San Antonio, Texas, USA. Electronic address: mahadevand@uthscsa.edu.
PMID: 38875929 DOI: 10.1016/j.neo.2024.101014
Abstract

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/G2/M) and cdt1-mKO (G1), 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.

Keywords

Alisertib; Aneuploidy; Cell cycle; Chromosomal instability; Polyploidy.

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