BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors
Por:
Bertran-Alamillo J., Giménez-Capitán A., Román R., Talbot S., Whiteley R., Floc’h N., Martínez-Pérez E., Martin M.J., Smith P.D., Sullivan I., Terp M.G., Saeh J., Marino-Buslje C., Fabbri G., Guo G., Xu M., Tornador C., Aguilar-Hernández A., Reguart N., Ditzel H.J., Martínez-Bueno A., Nabau-Moretó N., Gascó A., Rosell R., Pease J.E., Polanska U.M., Travers J., Urosevic J., Molina-Vila M.A.
Publicada:
1 ene 2023
Ahead of Print:
13 jul 2023
Resumen:
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.
Filiaciones:
Bertran-Alamillo J.:
Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital, C/ Sabino Arana 5-19, Barcelona, 08913, Spain
Giménez-Capitán A.:
Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital, C/ Sabino Arana 5-19, Barcelona, 08913, Spain
Román R.:
Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital, C/ Sabino Arana 5-19, Barcelona, 08913, Spain
Talbot S.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Whiteley R.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Floc’h N.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Martínez-Pérez E.:
Bioinformatics Unit, Fundación Instituto Leloir, Buenos Aires, C1405BWE, Argentina
Martin M.J.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Smith P.D.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Sullivan I.:
Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain
Instituto Oncológico Dr. Rosell, Hospital Universitario Dexeus, Barcelona, 08028, Spain
Terp M.G.:
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, 5000, Denmark
Saeh J.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA 02451, United States
Marino-Buslje C.:
Bioinformatics Unit, Fundación Instituto Leloir, Buenos Aires, C1405BWE, Argentina
Fabbri G.:
Translational Medicine, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA 02451, United States
Guo G.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA 02451, United States
Xu M.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, MA 02451, United States
Tornador C.:
Teresa Moretó Foundation and Wholegenix SL, Barcelona, 08021, Spain
Aguilar-Hernández A.:
Instituto Oncológico Dr. Rosell, Hospital Universitario Dexeus, Barcelona, 08028, Spain
Reguart N.:
Thoracic Oncology Unit, Department of Medical Oncology, Hospital Clínic, Barcelona, 08036, Spain
Ditzel H.J.:
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, 5000, Denmark
Department of Oncology, Odense University Hospital, Odense, 5000, Denmark
Martínez-Bueno A.:
Instituto Oncológico Dr. Rosell, Hospital Universitario Dexeus, Barcelona, 08028, Spain
Nabau-Moretó N.:
Teresa Moretó Foundation and Wholegenix SL, Barcelona, 08021, Spain
Gascó A.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Gaithersburg, MD 20878, United States
Rosell R.:
Instituto Oncológico Dr. Rosell, Hospital Universitario Dexeus, Barcelona, 08028, Spain
Germans Trias i Pujol Research Institute (IGTP), Badalona, 08916, Spain
Pease J.E.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Polanska U.M.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Travers J.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Urosevic J.:
Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, CB21 6GH, United Kingdom
Molina-Vila M.A.:
Laboratory of Oncology, Pangaea Oncology, Quiron Dexeus University Hospital, C/ Sabino Arana 5-19, Barcelona, 08913, Spain
gold, Green Published, All Open Access, Gold, Green
|