2. Academic Validation
  3. Aurora kinase A inhibition as a synthetic lethality strategy in ARID1A-mutated gastroenteropancreatic neuroendocrine carcinoma

Aurora kinase A inhibition as a synthetic lethality strategy in ARID1A-mutated gastroenteropancreatic neuroendocrine carcinoma

  • Cancer Lett. 2025 Sep 16:634:218033. doi: 10.1016/j.canlet.2025.218033.
Maria Urbanova 1,  Fabrice Viol 2,  Laura Ruiz-Cañas 3,  Efthymios Koniaris 4,  Rihards Saksis 5,  Sandra Batres-Ramos 3,  Julie Earl 6,  Agapi Kataki 7,  Verona Buocikova 1,  Monika Burikova 1,  Marina Cihova 1,  Lucia Rojikova 1,  Peter Makovicky 1,  Miroslava Matuskova 1,  Yvonne Kohl 8,  Andrea Riedmayer 8,  Marianna Makova 9,  Ladislav Baciak 10,  Daniel Gogola 11,  Olesja Rogoza 5,  Vita Rovite 5,  Bruno Sainz Jr 12,  Bozena Smolkova 13,  Joerg Schrader 14
Affiliations

Affiliations

  • 1 Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia.
  • 2 Medical Department, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg Eppendorf, 20246, Hamburg, Germany. Electronic address: f.viol@uke.de.
  • 3 Ramón y Cajal Health Research Institute (IRYCIS), Ramón y Cajal University Hospital. Ctra. Colmenar Viejo, 28034, Madrid, Spain; Department of Cancer, Instituto de Investigaciones Biomedicas Sols-Morreale (IIBM), CSIC-UAM, 28029, Madrid, Spain.
  • 4 Department of Pathology, Hippokration General, Hospital of Athens, Athens, 11527, Greece.
  • 5 Latvian Biomedical Research and Study Centre, Ratsupites Str 1-k1, LV-1067, Riga, Latvia.
  • 6 Ramón y Cajal Health Research Institute (IRYCIS), Ramón y Cajal University Hospital. Ctra. Colmenar Viejo, 28034, Madrid, Spain.
  • 7 First Department of Propaedeutic Surgery, Hippokration General Hospital of Athens, Athens, 11527, Greece.
  • 8 Department Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering IBMT, 66280, Sulzbach, Germany.
  • 9 Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia; Institute of Measurement Science, Slovak Academy of Sciences, 841 04, Bratislava, Slovakia.
  • 10 Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia.
  • 11 Institute of Measurement Science, Slovak Academy of Sciences, 841 04, Bratislava, Slovakia.
  • 12 Ramón y Cajal Health Research Institute (IRYCIS), Ramón y Cajal University Hospital. Ctra. Colmenar Viejo, 28034, Madrid, Spain; Department of Cancer, Instituto de Investigaciones Biomedicas Sols-Morreale (IIBM), CSIC-UAM, 28029, Madrid, Spain. Electronic address: bsainz@iib.uam.es.
  • 13 Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia. Electronic address: bozena.smolkova@savba.sk.
  • 14 Medical Department, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany. Electronic address: schrader.joerg@web.de.
PMID: 40962046 DOI: 10.1016/j.canlet.2025.218033
Abstract

Chemotherapy with cisplatin (CDDP) and etoposide (ETO) is the standard treatment for gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Despite high initial response rates, treatment-related toxicity and acquired resistance remain significant clinical challenges. No molecularly targeted therapies are currently established for this aggressive Cancer. Here, we evaluated Aurora Kinase inhibition with alisertib (ALI) as a synthetic lethality strategy in ARID1A-deficient GEP-NEC. Subcutaneous and orthotopic xenograft models were established in immunodeficient mice using the GEP-NEC-derived NT-38 cell line, and the therapeutic efficacy of ALI was compared with CDDP + ETO. Tumor responses were assessed by immunohistochemistry, Western blotting, and RNA Sequencing. To confirm ARID1A dependency, transient knockdown was induced in the pancreatic neuroendocrine NT-18LM cell line, demonstrating that ALI sensitivity is significantly enhanced in ARID1A-deficient cells. ALI achieved antitumor efficacy comparable to chemotherapy and was well tolerated, with minimal weight loss relative to CDDP + ETO. Distant metastases, an early feature of GEP-NEC, developed in five Animals over six weeks, two of which were treated with ALI and three controls. Transcriptomic profiling revealed convergence of both treatments on signal transduction, focal adhesion, receptor tyrosine kinase, and VEGFA-VEGFR2 signaling, while ALI uniquely enriched pathways related to pancreatic secretion, lipid metabolism, protein processing in the endoplasmic reticulum, and extracellular matrix organization. These findings establish Aurora Kinase inhibition as mechanistically distinct and selectively effective in ARID1A-deficient GEP-NEC. Given its efficacy, favorable tolerability, and ARID1A-dependent specificity, ALI may represent a promising alternative to platinum-based chemotherapy, offering a strong rationale for further development of mechanism-driven combination strategies for GEP-NEC.

Keywords

ARID1A; Alisertib; Chromatin remodeling; Gastroenteropancreatic neuroendocrine carcinoma; Synthetic lethality.

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