Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway

Author:

Hunter Jill E.1ORCID,Campbell Amy E.2,Hannaway Nicola L.1,Kerridge Scott1,Luli Saimir3,Butterworth Jacqueline A.1,Sellier Helene1,Mukherjee Reshmi1,Dhillon Nikita1,Sudhindar Praveen D.1,Shukla Ruchi1,Brownridge Philip J.2,Bell Hayden L.1,Coxhead Jonathan1,Taylor Leigh1,Leary Peter4,Hasoon Megan S.R.4,Collins Ian5,Garrett Michelle D.6,Eyers Claire E.2ORCID,Perkins Neil D.1ORCID

Affiliation:

1. 1Newcastle University Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K.

2. 2Centre for Proteome Research, Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.

3. 3Newcastle University Clinical and Translational Research Institute, Preclinical In Vivo Imaging (PIVI), Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K.

4. 4Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K.

5. 5Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton SM2 5NG, U.K.

6. 6School of Biosciences, Stacey Building, University of Kent, Canterbury, Kent CT2 7NJ, U.K.

Abstract

Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel−/− cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel−/− lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel−/− lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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