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

Hunter, Jill, Campbell, Amy, Hannaway, Nicola, Kerridge, Scott, Luli, Saimir, Butterworth, Jacqueline, Sellier, Helene, Mukherjee, Reshmi, Thomas, Huw, Brownridge, Philip
et al (show 8 more authors) (2021) Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway. [Preprint]

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Hunter et al BioRxiv 2021.05.26.445425v1.full.pdf - Submitted version

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We previously 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 c-rel -/- Eµ-Myc cells have an unexpected and major defect in the CHK1 pathway, with almost undetectable levels of CHK1 and CLSPN protein leading to therapeutic resistance to the highly specific CHK1 inhibitor (CHK1i) CCT244747. Similar downregulation of CHK1 levels was also seen in CCT244747 resistant U20S osteosarcoma cells. Further investigation revealed that downregulation of the deubiquitinase USP1 is responsible, at least in part, for these effects. Importantly, we demonstrate that c-rel -/- Eµ-Myc lymphoma cells survive though upregulation of compensatory PI3K/AKT pathway activity. Moreover, targeting this pathway with Pictilisib (GDC-0941) effectively killed c-rel -/- Eµ-Myc in vivo, while having no effect on wild type Eμ-Myc cells. This data reveals an NF-κB regulated pathway controlling CHK1 activity in cancer cells and identifies a potential mechanism for both acquiring and overcoming CHK1i resistance in cancer patients.

Item Type: Preprint
Uncontrolled Keywords: Lymphoma, Clinical Research, Cancer, Rare Diseases, Hematology, 2 Aetiology, 2.1 Biological and endogenous factors, Cancer
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 24 Jun 2021 08:01
Last Modified: 02 Apr 2024 09:25
DOI: 10.1101/2021.05.26.445425
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