Protein Arginine Methyltransferase 5 (PRMT5) and the ERK1/2 &amp; PI3K Pathways: A Case for PRMT5 Inhibition and Combination Therapies in Cancer

Sapir, Tzuriel; Shifteh, David; Pahmer, Moshe; Goel, Sanjay; Maitra, Radhashree

doi:10.1158/1541-7786.mcr-20-0745

Cited by 14 publications

(7 citation statements)

References 85 publications

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“…In fact, a pan-cancer analysis of copy number alterations shows that most often the PRMT5 region is amplified ( Figure 3 C). This agrees with findings that PRMT5 behaves like an oncogene [ 47 , 48 , 49 ] and consequently is overexpressed in most cancers [ 14 ]. We found three cases with PRMT5 homozygous deletions: a 76-year-old female with lung squamous cell carcinoma and two patients with kidney papillary renal cell carcinoma, an 82-year-old male and a 60-year-old female.…”

Section: Resultssupporting

confidence: 92%

Protein Arginine Methyltransferase 5 (PRMT5) Mutations in Cancer Cells

Rasheed

Bouley

Yoder

et al. 2023

IJMS

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Arginine methylation is a form of posttranslational modification that regulates many cellular functions such as development, DNA damage repair, inflammatory response, splicing, and signal transduction, among others. Protein arginine methyltransferase 5 (PRMT5) is one of nine identified methyltransferases, and it can methylate both histone and non-histone targets. It has pleiotropic functions, including recruitment of repair machinery to a chromosomal DNA double strand break (DSB) and coordinating the interplay between repair and checkpoint activation. Thus, PRMT5 has been actively studied as a cancer treatment target, and small molecule inhibitors of its enzymatic activity have already been developed. In this report, we analyzed all reported PRMT5 mutations appearing in cancer cells using data from the Catalogue of Somatic Mutations in Cancers (COSMIC). Our goal is to classify mutations as either drivers or passengers to understand which ones are likely to promote cellular transformation. Using gold standard artificial intelligence algorithms, we uncovered several key driver mutations in the active site of the enzyme (D306H, L315P, and N318K). In silico protein modeling shows that these mutations may affect the affinity of PRMT5 for S-adenosylmethionine (SAM), which is required as a methyl donor. Electrostatic analysis of the enzyme active site shows that one of these mutations creates a tunnel in the vicinity of the SAM binding site, which may allow interfering molecules to enter the enzyme active site and decrease its activity. We also identified several non-coding mutations that appear to affect PRMT5 splicing. Our analyses provide insights into the role of PRMT5 mutations in cancer cells. Additionally, since PRMT5 single molecule inhibitors have already been developed, this work may uncover future directions in how mutations can affect targeted inhibition.

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Section: Resultssupporting

confidence: 92%

Protein Arginine Methyltransferase 5 (PRMT5) Mutations in Cancer Cells

Rasheed

Bouley

Yoder

et al. 2023

IJMS

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“…As an epigenetic enzyme that modi es both core histones and non-histone substrates, PRMT5 is an emerging cancer therapeutic target and its speci c inhibitors have been developed and tested in many preclinical studies [44,45]. Recently several clinical trials using PRMT5-selective inhibitors were initiated for the treatment of advanced or metastatic tumors.…”

Section: Discussionmentioning

confidence: 99%

The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery

et al. 2023

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Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. TDRD1, a germ cell-speci c gene, is erroneously expressed in more than half of prostate tumors, but its role in prostate cancer development remains elusive. In this study, we identi ed a PRMT5-TDRD1 signaling axis that regulates the proliferation of prostate cancer cells. PRMT5 is a protein arginine methyltransferase essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Methylation of Sm proteins by PRMT5 is a critical initiation step for assembling snRNPs in the cytoplasm, and the nal snRNP assembly takes place in Cajal bodies in the nucleus. By mass spectrum analysis, we found that TDRD1 interacts with multiple subunits of the snRNP biogenesis machinery. In the cytoplasm, TDRD1 interacts with methylated Sm proteins in a PRMT5-dependent manner. In the nucleus, TDRD1 interacts with Coilin, the scaffold protein of Cajal bodies. Ablation of TDRD1 in prostate cancer cells disrupted the integrity of Cajal bodies, affected the snRNP biogenesis, and reduced cell proliferation. Taken together, this study represents the rst characterization of TDRD1 functions in prostate cancer development and suggests TDRD1 as a potential therapeutic target for prostate cancer treatment.GCA ATA GT-5') and the non-targeting control vector(U-009501-01-02) were obtained from Dharmacon (CO, USA). The ERG lentiviral sgRNA vector was purchased from Sigma-Aldrich with the sgRNA sequence: 5'-CCG TGG AGA GTT TTG TAA GGC T-3'. VCaP cells were transduced with lentivirus expressing Cas9 and then selected with 5 µg/ml blasticidin (Sigma-Aldrich #15205), followed by transduction with lentiviruses containing TDRD1 and ERG sgRNAs and control, followed by a selection of 5 µg/ml puromycin (Sigma-Aldrich #P8833). Cell growth assayVCaP, 22Rv1, and LNCaP cells were seeded at a density of 1 × 10 4 cells per well in at-bottomed 96-well plates and grew for 3-11 days. CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI, USA) was used to measure cell viability every other day, and the luminescence was determined by Synergy™ neo2 multi-mode reader (BioTek, Winooski, VT, USA).

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“…PRMT5 is overexpressed in the KRAS mutant colorectal cancer (CRC). [ 60 ] Currently a directed KRAS therapy is not formulated for cases of KRAS mutant CRC, making PRMT5 inhibition a plausible target.…”

Section: Discussionmentioning

confidence: 99%

Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review

Feustel

2022

Journal of Immunotherapy and Precision Oncology

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Protein arginine methyltransferase 5 (PRMT5) inhibitors are a new class of antineoplastic agents showing promising preliminary clinical efficacy. Targeting an enzyme involved in a wide array of cellular and transcriptional pro-oncogenic processes, this class offers multifaceted tumor-suppressive effects. Partial response has been seen in adenoid cystic carcinoma from both GSK3326595 and JNJ-64619178, with four cases of stable disease seen with PRT543. Highly significant is a durable complete response in isocitrate dehydrogenase 1-mutated glioblastoma multiforme with PRT811. Both alone and in combination with existing chemotherapies and immunotherapies, this class shows promising preliminary data, particularly in cancers with splicing mutations and DNA damage repair deficiencies. Further studies are warranted, and there are clinical trials to come whose data will be telling of the efficacy of PRMT5 inhibitors in both hematologic and solid malignancies. The aim of this study is to compile available results of PRMT5 inhibitors in oncology clinical trials.

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Protein Arginine Methyltransferase 5 (PRMT5) and the ERK1/2 & PI3K Pathways: A Case for PRMT5 Inhibition and Combination Therapies in Cancer

Cited by 14 publications

References 85 publications

Protein Arginine Methyltransferase 5 (PRMT5) Mutations in Cancer Cells

Protein Arginine Methyltransferase 5 (PRMT5) Mutations in Cancer Cells

The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery

Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review

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