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

Author:

Hunter Jill E.1ORCID,Campbell Amy E.2,Kerridge Scott1,Fraser Callum1,Hannaway Nicola L.1,Luli Saimir3,Ivanova Iglika1ORCID,Brownridge Philip J.2,Coxhead Jonathan1,Taylor Leigh1,Leary Peter4,Hasoon Megan S. R.4,Eyers Claire E.2ORCID,Perkins Neil D.1ORCID

Affiliation:

1. 1Newcastle University Biosciences Institute, Wolfson Childhood Cancer Research Centre, Newcastle University, Level 6, Herschel Building, Brewery Lane, Newcastle upon Tyne NE1 7RU, 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.

Abstract

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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