PRMT5 is a type II protein arginine methyltransferase. It is expressed in a number of cancers including pancreatic IPMN  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 .
|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 . 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 .
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 . 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).
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