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Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Eµ-Myc lymphoma cells

Lookup NU author(s): Dr Jill Hunter, Scott Kerridge, Dr Nicola Hannaway, Dr Saimir LuliORCiD, Dr Iglika Ivanova, Dr Jonathan Coxhead, Leigh Taylor, Dr Peter Leary, Dr Megan Hasoon, Professor Neil PerkinsORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2022 The Author(s). The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin on the Eµ-Myc mouse model of B-cell lymphoma, we discovered that both NF-κB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Eµ-Myc lymphomas depend on CHK1 activity to cope with high levels of DNA replication stress and consequent genomic instability, it was not clear how these mutant NF-κB subunit lymphomas were able to survive. To understand these survival mechanisms and to identify potential compensatory bypass signalling pathways in these lymphomas, we applied a multi-omics strategy. With c-Rel-/- Eµ-Myc lymphomas we observed high levels of Phosphatidyl-inositol 3-kinase (PI3K) and AKT pathway activation. Moreover, treatment with the PI3K inhibitor Pictilisib (GDC-0941) selectively inhibited the growth of reimplanted c-Rel-/- and RelAT505A, but not wild type (WT) Eµ-Myc lymphomas. We also observed up-regulation of a RHO/RAC pathway gene expression signature in both Eµ-Myc NF-κB subunit mutation models. Further investigation demonstrated activation of the RHO/RAC effector p21-activated kinase (PAK) 2. Here, the PAK inhibitor, PF-3758309 successfully overcame resistance of RelAT505A but not WT lymphomas. These findings demonstrate that up-regulation of multiple bypass pathways occurs in CHK1 inhibitor resistant Eµ-Myc lymphomas. Consequently, drugs targeting these pathways could potentially be used as either second line or combinatorial therapies to aid the successful clinical application of CHK1 inhibitors.


Publication metadata

Author(s): Hunter JE, Campbell AE, Kerridge S, Fraser C, Hannaway NL, Luli S, Ivanova I, Brownridge PJ, Coxhead J, Taylor L, Leary P, Hasoon MSR, Eyers CE, Perkins ND

Publication type: Article

Publication status: Published

Journal: Biochemical Journal

Year: 2022

Volume: 479

Issue: 19

Pages: 2131-2151

Online publication date: 14/10/2022

Acceptance date: 20/09/2022

Date deposited: 02/11/2022

ISSN (print): 0264-6021

ISSN (electronic): 1470-8728

Publisher: Portland Press

URL: https://doi.org/10.1042/BCJ20220103

DOI: 10.1042/BCJ20220103

PubMed id: 36240067


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Funding

Funder referenceFunder name
11022Bloodwise (Formerly Leukaemia and Lymphoma Research)
BB/R000182/1
C1443/A12750Cancer Research UK CRUK (open competition)
C1443/A22095Cancer Research UK CRUK (open competition)
BB/M012557/1

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