Cancer synthetic vulnerabilities to protein arginine methyltransferase inhibitors

Abstract

Protein arginine methylation is an abundant post-translational modification involved in the modulation of essential cellular processes ranging from transcription, post-transcriptional RNA metabolism, and propagation of signaling cascades to the regulation of the DNA damage response. Excitingly for the field, in the past few years there have been remarkable advances in the development of molecular tools and clinical compounds able to selectively and potently inhibit protein arginine methyltransferase (PRMT) functions. In this review, we first discuss how the somatic mutations that confer advantages to cancer cells are often associated with vulnerabilities that can be exploited by PRMTs' inhibition. In a second part, we discuss strategies to uncover synthetic lethal combinations between existing therapies and PRMT inhibitors.

Keywords: MTAP; MYC; PRMTs; Splicing factor mutations.

Fig.1.

A. The SAM cycle and MET salvage pathway. All PRMTs utilize SAM to catalyze their reaction, leading to the synthesis of monomethylarginine (MMA), asymmetrical dimethylarginine (ADMA) and symmetrical dimethylarginine (SDMA). MTA accumulates in MTAP null tumors and inhibits PRMT5. Abbreviations: MET=Methionine, SAM=S-adenosylmethionine, SAH=S-adenosylhomocysteine, HcY=Homocysteine, MTR1P=Methythioribose-1-phosphate, MTA=Methylthioadenosine, MAT=Methionine adenosyltransferases, MTAP=Methylthioadenosine phosphorylase B. The PRMT family. All PRMTs share a MT domain. Type I PRMTs (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6 and 8 are Type I enzymes catalyzing MMA and ADMA. PRMT5 and PRMT9 are type II enzymes generating MMA and SDMA. PRMT7 is a type III enzyme generating only MMA. Abbreviations: MT=MethylTransferase domain; SH3=Src homology 3; ZnF=zinc finger; TPR=tetratricopeptide. Numbers at the C-terminus correspond to the aminoacid length of human PRMTs.

Fig.2.

Synthetic vulnerabilities to PRMT inhibitors in cancer. A. In normal cells, the inhibition of gene B (in this example PRMT5), is compatible with cellular viability, granted that gene A is active. B. Synthetic dose lethality. In cells with oncogenic upregulation of a driver (in this example MYC), there is cellular dependence on gene B (i.e. PRMT5). C. Synthetic or Collateral vulnerability. In cells with mutation in a driver (e.g. SRSF2^P95H; U2AF1^S34F; SF3B1^K700E) there is cellular dependence on gene B (i.e. PRMT5). A specific sub-example of synthetic lethality, is when the deleted gene A is a passenger deletion (i.e. MTAP, co-deleted with the CDKN2A/B locus).

Fig.3.

A. Threshold model of PRMT5 activity. Normal post-mitotic cells (black bar) require a certain PRMT5 activity, cancer cells typically require 2–5 fold more (blue bar). In addition, normal cells can tolerate low PRMT5 activity (indicated by the bottom black line), while cancer cells require more. The therapeutic window in red is indicated. B. Threshold model of PRMT5 activity in MTAP null cells. As in A. with the addition of the basal lower activity of PRMT5 in MTAP null cells. C. Modalities of PRMT5 inhibition.