Abstract 2718: Targeting ribosome biogenesis with CX5461 as a potential treatment for melanoma and ovarian cancer

Abstract

Abstract Ribosome biogenesis provides the molecular machinery required for protein synthesis, thus it dictates the ability of a cell to grow and proliferate. We have recently demonstrated that inhibiting ribosome biogenesis with a small molecule that inhibits RNA Polymerase (POL) I driven transcription (CX5461) selectively killed B-lymphoma cells in vivo while maintaining a viable wild-type B cell population (Bywater et al., Cancer Cell 22: p51, 2012). The therapeutic effect was mediated via nucleolar disruption and activation of p53-dependent apoptotic signalling. Although this response was dependent on p53, cell lines from solid tumors with mutant p53 also respond to CX5461 (Drygin et al., Cancer Res 71: p1418, 2011). Dysregulation of both the PI3K and RAS/ERK pathways are common in ovarian cancer and BRAF is mutated and activated in over 50% of melanomas; a cancer that also commonly expresses wild type-p53. Given that both these pathways are critical regulators of ribosome biogenesis, we hypothesized that targeting ribosome biogenesis may be a new and potent approach to treating these cancers. To determine the efficacy of CX5461 a panel of ovarian cancer and melanoma cell lines were treated with CX5461 and cell proliferation assessed. The majority of cell lines were sensitive to CX5461 and differential gene expression between resistant and sensitive ovarian cancer cell lines revealed sensitivity was associated with signatures of increased MYC signalling and BRCA1 and 2 mutation. Gene expression and assessment of rDNA transcription suggested that resistance in both ovarian cancer and melanoma cell lines was associated with an inability of CX5461 to inhibit POL1 driven transcription. These studies indicate that targeting ribosome biogenesis and function may provide a new therapeutic option for treating ovarian cancer and melanoma. Citation Format: Karen E. Sheppard, Natalie Brajanovski, Katherine M. Hannan, Jessica Ahearn, Jason Ellul, Denis Drygin, Sean O'Brien, Grant McArthur, Ross D. Hannan, Richard B. Pearson. Targeting ribosome biogenesis with CX5461 as a potential treatment for melanoma and ovarian cancer. [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 2718. doi:10.1158/1538-7445.AM2014-2718