gsk3235025 and Neoplasms

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Deoxyadenosines; Female; Gene Deletion; Humans; Mice, Nude; Neoplasms; Phthalazines; Protein Binding; Protein-Arginine N-Methyltransferases; Purine-Nucleoside Phosphorylase; Thionucleosides; Xenograft Model Antitumor Assays

PRMT5 is an arginine methyltransferase that accounts for the vast majority of the symmetric methylation in cells. PRMT5 exerts its function when complexed with MEP50/WDR77. This activity is often elevated in cancer cells and correlates with poor prognosis, making PRMT5 a therapeutic target. To investigate the PRMT5 signaling pathway and to identify genes whose loss-of-function sensitizes cancer cells to PRMT5 inhibition, we performed a CRISPR/Cas9 genetic screen in the presence of a PRMT5 inhibitor. We identified known components of the PRMT5 writer/reader pathway including PRMT5 itself, MEP50/WDR77, PPP4C, SMNDC1 and SRSF3. Interestingly, loss of PRMT1, the major asymmetric arginine methyltransferase, also sensitizes cells to PRMT5 inhibition. We investigated the interplay between PRMT5 and PRMT1, and found that combinatorial inhibitor treatment of small cell lung cancer and pancreatic cancer cell models have a synergistic effect. Furthermore, MTAP-deleted cells, which harbor an attenuated PRMT5-MEP50 signaling pathway, are generally more sensitive to PRMT1 inhibition. Together, these findings demonstrate that there is a degree of redundancy between the PRMT5 and PRMT1 pathways, even though these two enzymes deposit different types of arginine methylation marks. Targeting this redundancy provides a vulnerability for tumors carrying a co-deletion of MTAP and the adjacent CDKN2A tumor suppressor gene.

Topics: A549 Cells; Animals; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Ethylenediamines; Gene Deletion; Humans; Isoquinolines; MCF-7 Cells; Mice, Knockout; Neoplasms; Protein-Arginine N-Methyltransferases; Pyrimidines; Pyrroles; Repressor Proteins; Signal Transduction

The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.

Topics: Cell Line, Tumor; Deoxyadenosines; Enzyme Inhibitors; Gene Deletion; Humans; Isoquinolines; Neoplasms; Protein-Arginine N-Methyltransferases; Purine-Nucleoside Phosphorylase; Pyrimidines; Thionucleosides; Transcription Factors