Enhanced rates of ribosome biogenesis and ribosome translational activity are key features of malignant cells driving their enhanced growth and proliferation. The survival of MYC-driven cancer cells in particular is exquisitely dependent on the sustained generation of ribosomal RNA (rRNA) and ribosomal proteins (RP) as well as sustained rates of eIF4E-mediated cap-dependent protein translation [1-3]. The transcription of the rRNA encoding genes (rDNA) by RNA polymerase I (Pol I) has recently been demonstrated to be a therapeutic target for MYC-driven cancers, with the novel small molecule CX-5461 mediating the selective killing of B-lymphoma cells in vivo while maintaining the viable wild-type B-cell population [2]. However the eventual development of resistance to CX-5461 in many cancer types has driven the search for rational combination strategies. It was hypothesized that simultaneous targeting of the PI3K/AKT/mTOR signalling pathway that regulates the biogenesis and translational activity of the ribosome would cooperate with CX-5461 to delay disease relapse and extend the survival of B-lymphoma bearing mice.
Using the Eμ-Myc model of B-cell lymphoma we demonstrate that multiple pharmacological inhibitors of the PI3K/AKT/mTOR pathway suppress transcription of the rRNA genes and induce cell death similar to CX-5461. However in contrast to CX-5461 where B-lymphoma cell apoptosis was a consequence of nucleolar disruption and activation of RP-MDM2-P53 nucleolar stress response [4], the coordinated suppression of both rRNA synthesis and RP synthesis by PI3K/AKT/mTOR pathway inhibitors blocked increase the pool of free RPs necessary to suppress MDM2 E3 ligase and promote p53 stability and activation. Apoptosis induced by the pathway inhibitors was instead linked to the up-regulation of the pro-apoptotic BH3-only protein BMF. Furthermore, we demonstrate that combined treatment of Eμ-Myc tumour-bearing mice with CX-5461 and the mTORC1 inhibitor Everolimus delayed relapse and doubled the survival of tumor bearing mice compared to single agent treatment.
These data demonstrate that the coordinated targeting of the network controlling the synthesis and activity of the ribosome is a novel and potent approach for the treatment of MYC driven tumours. It therefore provides a rationale to combine such drugs in the clinic for the treatment of MYC driven cancer.