2. Academic Validation
  3. BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors

BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors

  • Mol Cancer. 2023 Jul 13;22(1):110. doi: 10.1186/s12943-023-01815-w.
Jordi Bertran-Alamillo 1,  Ana Giménez-Capitán # 1,  Ruth Román # 1,  Sara Talbot # 2,  Rebecca Whiteley # 2,  Nicolas Floc'h 2,  Elizabeth Martínez-Pérez 3,  Matthew J Martin 2,  Paul D Smith 2,  Ivana Sullivan 4 5,  Mikkel G Terp 6,  Jamal Saeh 7,  Cristina Marino-Buslje 3,  Giulia Fabbri 8,  Grace Guo 7,  Man Xu 7,  Cristian Tornador 9,  Andrés Aguilar-Hernández 5,  Noemí Reguart 10,  Henrik J Ditzel 6 11,  Alejandro Martínez-Bueno 5,  Núria Nabau-Moretó 9,  Amaya Gascó 12,  Rafael Rosell 5 13,  J Elizabeth Pease 2,  Urszula M Polanska 2,  Jon Travers 2,  Jelena Urosevic # 14,  Miguel A Molina-Vila # 15
Affiliations

Affiliations

  • 1 Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital, C/ Sabino Arana 5-19, 08913, Barcelona, Spain.
  • 2 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, UK.
  • 3 Bioinformatics Unit, Fundación Instituto Leloir, Buenos Aires, C1405BWE, Argentina.
  • 4 Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain.
  • 5 Instituto Oncológico Dr. Rosell, Hospital Universitario Dexeus, Barcelona, 08028, Spain.
  • 6 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, 5000, Denmark.
  • 7 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA, 02451, USA.
  • 8 Translational Medicine, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA, 02451, USA.
  • 9 Teresa Moretó Foundation and Wholegenix SL, Barcelona, 08021, Spain.
  • 10 Thoracic Oncology Unit, Department of Medical Oncology, Hospital Clínic, Barcelona, 08036, Spain.
  • 11 Department of Oncology, Odense University Hospital, Odense, 5000, Denmark.
  • 12 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, 20878, USA.
  • 13 Germans Trias i Pujol Research Institute (IGTP), Badalona, 08916, Spain.
  • 14 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, UK. jelena.urosevic@astrazeneca.com.
  • 15 Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital, C/ Sabino Arana 5-19, 08913, Barcelona, Spain. mamolina@panoncology.com.
  • # Contributed equally.
PMID: 37443114 DOI: 10.1186/s12943-023-01815-w
Abstract

Background: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora Kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection.

Methods: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice.

Results: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors.

Conclusions: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

Keywords

AURKB inhibitor; Abrogation; BID; Biomarker; CASP-2; Cell cycle; Spindle assembly checkpoint (SAC); TTK inhibitor; Tumor.

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