Abstract 2735: Multi-point targeting of the synthetic lethal interactions between Myc, ribosome biogenesis and ribosome function cooperates to treat B-cell lymphoma
Authors: Pearson Richard B. , Devlin Jennifer R. , Hannan Katherine M. , Hein Nadine , Bywater Megan J. , Poortinga Gretchen , Cameron Donald , Drygin Denis , O'Brien Sean , Cullinane Carleen , McArthur Grant A. , Hannan Ross D. 
Published: May 2015

Abstract
We recently demonstrated that transcription of the ribosomal genes (rRNA) by RNA Polymerase I (Pol I) can be therapeutically targeted with a novel small molecule, CX-5461, to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B-cell population (Bywater et al Cancer Cell 2012; Bywater et al Nature Reviews Cancer 2013). The therapeutic effect was a consequence of nucleolar disruption, activation of ribosomal protein (Rp)-MDM2-P53 nucleolar stress response and apoptosis. We have recently launched a first-in-human clinical trial of CX-5461 in patients with hematological malignancies and although our pre-clinical data indicate immense potential of Pol I targeting for cancer therapy, some cancers still develop resistance. We hypothesized that simultaneously targeting the ribosome at multiple steps will extend survival. Thus we tested pharmacological inhibitors of PI3K/AKT/mTOR signalling in combination with CX-5461 as the former pathway is known to potently regulate both translational activity (Jefferies et al EMBO J, 1997; Pourdehnad M et al PNAS 2013) and ribosome biogenesis (Chan et al Science Signaling 2011; Devlin et al FEBS J 2013; Wall et al Cancer Discovery 2013).
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. Unexpectedly however, PI3K/AKT/mTOR pathway blockade is not associated with nucleolar disruption, or activation of the Rp/MDM2/p53 nucleolar stress pathway. This is because inhibition of PI3K/AKT/mTOR signalling suppresses both rRNA synthesis and ribosomal protein synthesis equally and therefore does not increase the pool of free Rps necessary to suppress MDM2 E3 ligase that regulates p53 stability. Furthermore, we demonstrate that combined treatment of Eμ-Myc tumor-bearing mice with CX-5461 and Everolimus delayed relapse compare to single agent and significantly extended survival of tumor bearing mice.
These data demonstrate that dual targeting of the ribosome by selectively inhibiting Pol I transcription and inhibition of key signaling molecules regulating ribosome synthesis and function combine to potently treat MYC driven tumors. It therefore provides a rationale to combine such drugs in the clinic for the treatment of MYC driven cancer.
Citation Format: Richard B. Pearson, Jennifer R. Devlin, Katherine M. Hannan, Nadine Hein, Megan J. Bywater, Gretchen Poortinga, Donald Cameron, Denis Drygin, Sean O'Brien, Carleen Cullinane, Grant A. McArthur, Ross D. Hannan. Multi-point targeting of the synthetic lethal interactions between Myc, ribosome biogenesis and ribosome function cooperates to treat B-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2735. doi:10.1158/1538-7445.AM2014-2735