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SAM Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

ABSTRACT: SAM Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

PROVIDER: PRJNA730796 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14575418_1.fastq.gz	Fastqsanger.gz
	SRR14575418_2.fastq.gz	Fastqsanger.gz
	SRR14575419_1.fastq.gz	Fastqsanger.gz
	SRR14575419_2.fastq.gz	Fastqsanger.gz
	SRR14575420_1.fastq.gz	Fastqsanger.gz

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SAM Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

Project description:Protein arginine methyltransferase 5 (PRMT5) over-expression in hematological and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the co-factor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of NSCLC cancer cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.

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Project description:Inducing senescence in cancer cells is emerging as a new therapeutic strategy. We tested the senescence induction of palbociclib and indisulam or PF-06873600 in A549 and PF-06873600 in SUM159 cells, and profiled these for senescence associated gene signatures.

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Sulfur assimilation improves SAM-dependent methylation

Project description:We employed omic data and conducted comparative analysis in Saccharomyces cerevisiae strains with different S-adenosine-L-methionine (SAM) level. This strategy can help us locate the limiting factor for SAM availability. We found sulfur assimilation emerged as the most significantly enriched pathway and further confirmed that sulfur assimilation was the dominant limiting step of SAM biosynthesis in the whole cell system.

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Genetic Contribution to the Abuse Liability of Oxycodone

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Transcriptome analyses of narrow sheath shoot apical meristem (SAM) vs non-mutant SAM

Project description:Loss of function mutations in the narrow sheath (ns) duplicate genes (ns1 and ns2) cause the deletion of a mediolateral domain from maize leaves. The ns genes encode duplicate WUSCHEL1-like homeobox (WOX) putative transcription factors that function redundantly and non-cell autonomously to direct recruitment of leaf founder cell-initials in a lateral domain of the shoot apex. In order to investigate the genetic mechanisms of NS1 gene function, SAM-specific transcriptional profiling of narrow sheath mutant1-R comparing to that of nonmutant using laser microdissection microarray. Whole SAMs were laser-microdissected from ns1-R mutant and non-mutant seedlings grown under the same controlled conditions. Microarray profiles were generated for 37,662 maize cDNAs contained on gene chips SAM 1.1, SAM 2.0 and SAM 3.0 (For details, see the the Iowa State University Center for Plant Genomics website). Keywords: Genetic modification

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