Oral Presentation Australasian Melanoma Conference 2018

Overcoming therapy induced reprogramming of metabolism in BRAFV600 melanoma (55513)

Lorey K Smith 1 2 , Tiffany Parmenter 1 , Eric Kusnadi 1 2 , Margarete Kleinshmidt 1 , Jian Kang 1 2 , Teresa Ward 1 , Aparna Rao 1 2 , Karen Sheppard 1 2 3 , Kaylene Simpson 4 , Tony Tiganis 1 5 , Rick Pearson 1 2 3 , Grant McArthur 1 2 6 7 8
  1. Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Sir Peter McCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Biochemistry, University of Melbourne, Melbourne, VIC, Australia
  4. Victorian Centre of Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. Cellular Signalling and Human Disease Laboratory, Monash University, Melbourne, VIC, Australia
  6. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  7. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Melbourne, Victoria, Australia
  8. Translational Research Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes appear to be limited by a drug adaptation and tolerance phase where initial pathway inhibition induces oncogenic network rewiring to allow cell survival 1. This rewiring precedes acquired resistance and thus represents an opportunity to prolong responses and prevent or delay resistance. Metabolic adaptation in response to MAPK pathway inhibition is well established in melanoma, and several metabolic vulnerabilities including glycolysis, oxidative phosphorylation and glutaminolysis have been linked with therapeutic response, adaptation and resistance 2-5. To examine how therapy reprograms metabolism we performed a genome-wide RNAi screen in melanoma cells following BRAF inhibition in the therapeutic adaptation phase prior to acquired resistance. This approach uncovered mRNA transport and translation, including RNA binding kinase UHMK1, as a critical regulator of metabolic responses to BRAF inhibition. Depletion of UHMK1 enhanced BRAF inhibitor sensitivity, synergistically suppressing glycolysis, proliferation, and viability, whilst analysis of mitochondrial metabolism revealed reduced spare respiratory capacity, ATP production and glutamine dependency. Together this data identifies a multifaceted role for UHMK1 in metabolic responses to BRAF inhibition. Mechanistically, polysome profiling and de novo protein synthesis assays revealed selective translation of mRNA encoding metabolic enzymes in cells adapting to BRAF inhibition, and critically, we show this is UHMK1 dependent. Moreover, we demonstrate UHMK1 interacts with mRNA encoding these enzymes, and regulates their nuclear-cytoplasmic transport. Our data suggests UHMK1 regulates therapy-induced metabolic adaptation by controlling the abundance of metabolic enzymes through the export and translation of the mRNA that encode them. We propose this pathway is an attractive therapeutic target to improve efficacy of MAPK pathway inhibitors by targeting the process of adaptation itself, rather than the outcome, as a next generation combination therapy.

References

  1. Smith MP, Brunton H, Rowling EJ, et al. Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy. Cancer Cell. Mar 14 2016;29(3):270-284.
  2. Parmenter TJ, Kleinschmidt M, Kinross KM, et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. Apr 2014;4(4):423-433.
  3. Haq R, Shoag J, Andreu-Perez P, et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell. Mar 18 2013;23(3):302-315.
  4. Hernandez-Davies JE, Tran TQ, Reid MA, et al. Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J Transl Med. 2015;13:210.
  5. Baenke F, Chaneton B, Smith M, et al. Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells. Mol Oncol. Aug 20 2015.