| Title: |
Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Em-Myc lymphoma cells |
| Authors: |
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 |
| Publisher Information: |
Portland Press Ltd. |
| Publication Year: |
2022 |
| Collection: |
The University of Liverpool Repository |
| Description: |
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 RelA T505A 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 RelA T505A , 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 RelA T505A 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
0264-6021 |
| Relation: |
https://livrepository.liverpool.ac.uk/3165684/1/Hunter%20bcj-2022-0103%20Bypass.pdf; Collapse authors list. Hunter, JE, Campbell, AE, Kerridge, S, Fraser, C, Hannaway, NL, Luli, S, Ivanova, I, Brownridge, PJ, Coxhead, J, Taylor, L et al (show 4 more authors) , Leary, P, Hasoon, MSR, Eyers, CE orcid:0000-0002-3223-5926 and Perkins, ND (2022) Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Em-Myc lymphoma cells Biochemical Journal, 479 (19). pp. 2131-2151. ISSN 0264-6021, 1470-8728 |
| DOI: |
10.1042/bcj20220103 |
| Availability: |
https://livrepository.liverpool.ac.uk/3165684/; https://doi.org/10.1042/bcj20220103 |
| Accession Number: |
edsbas.E54354EF |
| Database: |
BASE |