BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors
Bertran-Alamillo, Jordi (Hospital Universitari Dexeus - Grup Quirónsalud)
Giménez-Capitán, Ana (Hospital Universitari Dexeus - Grup Quirónsalud)
Román, Ruth (Hospital Universitari Dexeus - Grup Quirónsalud)
Talbot, Sara (AstraZeneca Oncology R&D)
Whiteley, Rebecca (AstraZeneca Oncology R&D)
Floc'h, Nicolas (AstraZeneca Oncology R&D)
Martínez-Pérez, Elizabeth (Fundación Instituto Leloir (Buenos Aires, Argentina))
Martin, Matthew J. (AstraZeneca Oncology R&D)
Smith, Paul D. (AstraZeneca Oncology R&D)
Sullivan, Ivana (Institut d'Investigació Biomèdica Sant Pau)
Terp, Mikkel G. (University of Southern Denmark)
Saeh, Jamal (AstraZeneca Oncology R&D)
Marino-Buslje, Cristina (Fundación Instituto Leloir (Buenos Aires, Argentina))
Fabbri, Giulia (AstraZeneca Oncology R&D)
Guo, Grace (AstraZeneca Oncology R&D)
Xu, Man (AstraZeneca Oncology R&D)
Tornador, Cristian (Teresa Moretó Foundation and Wholegenix SL)
Aguilar-Hernández, Andrés (Hospital Universitari Dexeus (Barcelona, Catalunya))
Reguart, Noemi (Hospital Clínic i Provincial de Barcelona)
Ditzel, Henrik J. (Odense University Hospital (Dinamarca))
Martínez-Bueno, Alejandro (Hospital Universitari Dexeus (Barcelona, Catalunya))
Nabau-Moretó, Núria (Teresa Moretó Foundation and Wholegenix SL)
Gascó, Amaya (AstraZeneca Oncology R&D)
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Pease, J. Elizabeth (AstraZeneca Oncology R&D)
Polanska, Urszula M. (AstraZeneca Oncology R&D)
Travers, Jon (AstraZeneca Oncology R&D)
Urosevic, Jelena (AstraZeneca Oncology R&D)
Molina-Vila, Miguel A. (Hospital Universitari Dexeus - Grup Quirónsalud)
Universitat Autònoma de Barcelona

Date:	2023
Abstract:	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. 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. 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. 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	AURKB inhibitor ; Abrogation ; BID ; Biomarker ; CASP-2 ; Cell cycle ; Spindle assembly checkpoint (SAC) ; TTK inhibidor ; Tumor
Published in:	Molecular cancer, Vol. 22 Núm. 1 (december 2023) , p. 110, ISSN 1476-4598

DOI: 10.1186/s12943-023-01815-w
PMID: 37443114

24 p, 13.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles