Invited Speaker Oral 2nd Australian Cancer and Metabolism Meeting 2017

Reprogramming of cellular metabolism associated with resistance to cancer therapies targeting the ribosome (#25)

Rick Pearson 1 2 3 4 , Eric P Kusnadi 2 3 , Jian Kang 2 , Katherine M Hannan 4 5 , Anna S Trigos 2 3 , David L Goode 2 6 , Vincent Van Hoef 7 , Ola Larsson 7 , David P De Souza 8 , Dedreia Tull 8 , Malcolm McConville 4 8 , Ross D Hannan 1 2 3 4 5 9
  1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  2. Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  4. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia
  5. ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Acton, ACT, Australia
  6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  7. Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden
  8. Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC, Australia
  9. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Malignancies including haematological, prostate and ovarian cancers (OVCAs) are characterized by deregulated signaling through the PI3K/RAS/MYC network and are associated with elevated rates of ribosome biogenesis and mTORC1/eIF4E-driven protein synthesis suggesting they may be vulnerable to therapeutic strategies that target the ribosome. We have demonstrated that the specific small molecule inhibitor of RNA Polymerase I transcription (CX-5461) induces a period of complete disease remission in mice transplanted with Eμ-MYC lymphomas while maintaining a normal B-cell population. Furthermore, CX-5461 and Everolimus (mTORC1 inhibitor) co-treatment more than doubled the survival of Eμ-MYC lymphoma-bearing mice. (Devlin et al., 2016, Cancer Discovery). However, despite the improved survival, the Eμ-MYC lymphoma-bearing mice eventually became resistant to this combination therapy and thus succumbed to disease.

In order to examine the mechanisms underlying this resistance to ribosome-targeting therapy, we undertook metabolic profiling of early passage cell lines from lymph nodes isolated from the mice at disease onset. Our data from a (GC-MS)-based metabolomics analysis demonstrated that the combination therapy-resistant cells have upregulated metabolic activity compared to single-agent resistant and sensitive cells. The resistant cells produce more ATP and are characterised by significantly higher levels of glycolytic intermediates such as fructose 1,6-bisphosphate and 3-phosphoglycerate as well as increased lactate content. To compliment this study, we used poly(ribo)some profiling, a high-throughput, genome-wide analysis of the translatome, to investigate on a global scale whether these metabolic alterations are driven by changes in mRNA translation. Polysome-associated mRNAs were analysed by RNA-seq and the analysis revealed that the combination therapy-resistant cells had enhanced translation of mRNAs encoding components of the Complex I of the mitochondrial electron transport chain, as well as proteins associated with the cyclic-AMP (cAMP) signalling pathway. These findings raise the possibility that therapies that modulate cellular ATP or cAMP metabolism may improve the efficacy of inhibitors of ribosome biogenesis and function, providing new therapeutic options for treating resistant disease.