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

Hunter, Jill E, Campbell, Amy E, Kerridge, Scott, Fraser, Callum, Hannaway, Nicola L, Luli, Saimir, Ivanova, Iglika, Brownridge, Philip J, Coxhead, Jonathan, Taylor, Leigh
et al (show 4 more authors) (2022) Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant E?-Myc lymphoma cells. BIOCHEMICAL JOURNAL, 479 (19). pp. 2131-2151.

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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.

Item Type: Article
Uncontrolled Keywords: Animals, Mice, Transgenic, Mice, Lymphoma, Inositol, NF-kappa B, Proto-Oncogene Proteins c-myc, Protein Kinase Inhibitors, Up-Regulation, Proto-Oncogene Proteins c-akt, p21-Activated Kinases, Phosphatidylinositol 3-Kinases, Phosphatidylinositol 3-Kinase
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: 21 Oct 2022 08:34
Last Modified: 18 Jan 2023 19:49
DOI: 10.1042/BCJ20220103
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3165684