The mitotic checkpoint kinase BUB1 is a direct and actionable target of MYB in adenoid cystic carcinoma

Author:

Cicirò Ylenia1,Ragusa Denise2ORCID,Nevado Paloma Tejera3,Lattanzio Rossano4,Sala Gianluca4ORCID,DesRochers Tessa5,Millard Melissa5,Andersson Mattias K.3ORCID,Stenman Göran3,Sala Arturo1ORCID

Affiliation:

1. Department of Life Sciences, Centre for Inflammation Research and Molecular Medicine (CIRTM) Brunel University London Uxbridge UK

2. Department of Life Sciences, Centre for Genomic Engineering and Maintenance (CenGEM) Brunel University London Uxbridge UK

3. Sahlgrenska Center for Cancer Research Department of Pathology University of Gothenburg Sweden

4. Center for Advanced Studies and Technology (CAST); Department of Innovative Technologies in Medicine & Dentistry University of Chieti‐Pescara Italy

5. Kiyatec Greenville SC USA

Abstract

Adenoid cystic carcinoma (ACC) is a head and neck cancer that frequently originates in salivary glands, but can also strike other exocrine glands such as the breast. A key molecular alteration found in the majority of ACC cases is MYB gene rearrangements, leading to activation of the oncogenic transcription factor MYB. In this study, we used immortalised breast epithelial cells and an inducible MYB transgene as a model of ACC. Molecular profiling confirmed that MYB‐driven gene expression causes a transition into an ACC‐like state. Using this new cell model, we identified BUB1 as a targetable kinase directly controlled by MYB, whose pharmacological inhibition caused MYB‐dependent synthetic lethality, growth arrest and apoptosis of patient‐derived cells and organoids.

Funder

Sjöbergstiftelsen

Adenoid Cystic Carcinoma Research Foundation

Cancerfonden

Oracle Cancer Trust

Fondazione AIRC per la ricerca sul cancro ETS

Publisher

Wiley

Subject

Cell Biology,Genetics,Molecular Biology,Biochemistry,Structural Biology,Biophysics

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