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.
ISSN 0264-6021, 1470-8728
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Hunter bcj-2022-0103 Bypass.pdf - Published version Download (16MB) | Preview |
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.
| 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 & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 21 Oct 2022 08:34 |
| Last Modified: | 16 Jun 2026 09:29 |
| DOI: | 10.1042/BCJ20220103 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165684 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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