| First Author | Hunter JE | Year | 2022 |
| Journal | Biochem J | Volume | 479 |
| Issue | 19 | Pages | 2131-2151 |
| PubMed ID | 36240067 | Mgi Jnum | J:332173 |
| Mgi Id | MGI:7411033 | Doi | 10.1042/BCJ20220103 |
| Citation | Hunter JE, et al. (2022) Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Emicro-Myc lymphoma cells. Biochem J 479(19):2131-2151 |
| abstractText | 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 Emicro-Myc mouse model of B-cell lymphoma, we discovered that both NF-kappaB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Emicro-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-kappaB 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-/- Emicro-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) Emicro-Myc lymphomas. We also observed up-regulation of a RHO/RAC pathway gene expression signature in both Emicro-Myc NF-kappaB 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 Emicro-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. |
