PRMT5 a promising synthetic lethal drug target for an estimated 30% of pancreatic cancers

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PRMT5 is a type II protein arginine methyltransferase. It is expressed in a number of cancers including pancreatic IPMN [1] and PDAC (GEO database). It is expressed by all 44 pancreatic cancer cell lines in the cancer cell line encyclopedia (CCLE- figure 1). In leukaemia and lymphoma cells it has been shown that PRMT5 suppresses the transcription of the RB family of tumour suppressors [2].

 CCLE
Figure 1: Comparison of PRMT5, MTAP and CDKN2A mRNA expression in 44 pancreatic cancer cell lines (data source CCLE). RMA = robust multiarray average (mRNA expression).

5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway [3]. The MTAP gene is located next to the tumour suppressor CDKN2A and its expression is often lost as a result of CDKN2A deletion during cancer progression. Indeed 30% of the pancreatic cancer cell lines in the CCLE have MTAP deletion associated with loss of CDKN2A expression (figure 1). MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which has been found to inhibit PRMT5 methyltransferase activity [3].

In cancer cells PRMT5 expression and activity prevents programmed cell death from occurring. Cancer cells express high levels of PRMT5 (figure 1) such that MTAP deletion does not fully inhibit PRMT5’s activity. However the cancer cells are sensitive to further drug inhibition of PRMT5 compared to normal cells due to inhibition of PRMT5 by MTA. If PRMT5 is fully inhibited tumour suppressor proteins such as the RB family are able to trigger cancer cell death. This makes PRMT5 an excellent target for drug development.

PRMT5 is required in normal tissues for instance it is essential for sustaining normal adult hematopoiesis [4]. However due to MTAP deletion cancer cells are more sensitive to PRMT5 inhibition than normal cells so it should be possible to optimise PRMT5 drug dosing such that it is fully inhibited in cancer but only partially in normal cells. This would be much better than traditional chemotherapeutics which are fully toxic to both normal and cancer cells. PRMT5 is a promising synthetic lethal drug target for roughly 30% of pancreatic cancers (figure 1).

Refs

  1. Sato, Norihiro, Noriyoshi Fukushima, Anirban Maitra, Christine A. Iacobuzio-Donahue, N. Tjarda van Heek, John L. Cameron, Charles J. Yeo, Ralph H. Hruban, and Michael Goggins. ‘Gene Expression Profiling Identifies Genes Associated with Invasive Intraductal Papillary Mucinous Neoplasms of the Pancreas’. The American Journal of Pathology 164, no. 3 (2004): 903–14. Article – Pubmed Central.
  2. Wang, L., S. Pal, and S. Sif. ‘Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells’. Molecular and Cellular Biology 28, no. 20 (15 October 2008): 6262–77. doi:10.1128/MCB.00923-08.
  3. Mavrakis, Konstantinos J., E. Robert McDonald, Michael R. Schlabach, Eric Billy, Gregory R. Hoffman, Antoine deWeck, David A. Ruddy, et al. ‘Disordered Methionine Metabolism in MTAP/CDKN2A Deleted Cancers Leads to Dependence on PRMT5’. Science, 11 February 2016, aad5944. doi:10.1126/science.aad5944.
  4. Liu, Fan, Guoyan Cheng, Pierre-Jacques Hamard, Sarah Greenblatt, Lan Wang, Na Man, Fabiana Perna, et al. ‘Arginine Methyltransferase PRMT5 Is Essential for Sustaining Normal Adult Hematopoiesis’. Journal of Clinical Investigation 125, no. 9 (1 September 2015): 3532–44. doi:10.1172/JCI81749.
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