Poster Presentation 30th Lorne Cancer Conference 2018

RNA binding kinase UHMK1 facilitates therapy induced metabolic adaptation in BRAFV600 melanoma (#268)

Lorey Smith 1 , Tiffany Parmenter 1 , Eric Kusnadi 1 , Margarete Kleinshmidt 1 , Teresa Ward 1 , Jian Kang 1 , Aparna Rao 1 , Tariq Butt 2 , Karen Sheppard 1 , Kaylene Simpson 3 , Tony Tiganis 1 2 , Vihandha Wickramasinghe 1 , Rick Pearson 1 , Grant McArthur 1 4 5 6 7
  1. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Monash University, Melbourne, Vic, Australia
  3. Victorian Centre of Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. Sir Peter McCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  5. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  6. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Melbourne, Victoria, Australia
  7. Translational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Cancer cells rewire their metabolism in response to cellular stresses, and to satisfy the demands of growth and proliferation. One of the principal metabolic reprogramming events in cancer cells involves aerobic glycolysis or the “Warburg effect”. In aerobic conditions normal cells metabolize glucose using oxidative metabolism in mitochondria, whereas cancer cells metabolize glucose to lactate using aerobic glycolysis in the cytoplasm. In the setting of melanoma, the BRAFV600E oncogene regulates aerobic glycolysis and sensitivity to the BRAF inhibitor Vemurafenib (Vem) correlates with glycolytic response. Notably, metabolic reprogramming involving oxidative metabolism has also been associated with early drug adaptation and the development of resistance to BRAF inhibitors. To identify mechanisms of BRAFV600E-driven metabolic reprogramming and response to Vem, we performed a genome wide glycolysis screen in BRAFV600E melanoma cells, in the presence or absence of Vem. This approach uncovered RNA processing and translation pathways as major nodes in the BRAFV600E glycolysis network, including the RNA binding protein kinase UHMK1. Depletion of UHMK1 enhanced Vem sensitivity, synergistically suppressing glycolysis, proliferation, and viability, while analysis of oxidative metabolism revealed reduced spare respiratory capacity, glutamine dependency and ATP production. Thus UHMK1 plays a role in adaptive metabolic responses to Vem. Analysis of mRNA translation using polysome profiling demonstrated selective translation of metabolic enzymes as cells adapt to BRAF inhibition, despite global inhibition of protein synthesis. Importantly, this adaptive translation program was inhibited by depletion of UHMK1. Our data provides evidence of a novel therapy induced mRNA translation mechanism regulating metabolic adaptation in melanoma. We propose that inhibition of this pathway represents an attractive therapeutic target to improve efficacy of BRAF inhibitors by preventing metabolic adaptation in BRAFV600E melanoma.