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

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 E mu-Myc mouse model of B-cell lymphoma, we discovered that both NF-kappa B subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since E mu-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-kappa B 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-/- E mu-Myc lymphomas we observed high levels of Phosphatidyl-inositol 3-kinase (PI3K) and AKT pathway activation. Moreover, treatment with the PI3K inhibitor Pictilisib (GDC0941) selectively inhibited the growth of reimplanted c-Rel-/- and RelAT505A, but not wild type (WT) E mu-Myc lymphomas. We also observed up-regulation of a RHO/RAC pathway gene expression signature in both E mu-Myc NF-kappa B 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 E mu-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.

Automated summary

In this study, we discovered the up-regulation of multiple bypass pathways in lymphomas with mutant NF-kappa B subunits, and demonstrated that drugs targeting these pathways could potentially be used to aid the successful clinical application of CHK1 inhibitors.