SAM Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance
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PROVIDER: PRJNA730796 | ENA |
REPOSITORIES: ENA
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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.
2021-11-09 | GSE174615 | GEO
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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Project description:The recessive mutation ragged seedling2-R (rgd2-R) conditions defective lateral development of maize leaves. Although dorsiventral patterning is established in rgd2-R mutant leaves, some swapping of adaxial/abaxial epidermal identity may occur. Molecular analyses indicate that RGD2 is required for the coordination of dorsiventral and lateral patterning during maize leaf development, yet the RGD2 gene product and the mechanisms of RGD2 function are unknown. In order to investigate the genetic mechanisms downstream of RGD2 gene function, SAM-specific transcriptional profiling of rgd2-R is compared to that of nonmutant using laser microdissection microarray. Whole SAMs were laser-microdissected from rgd2-R mutant and non-mutant seedlings grown under the same controlled conditions. Microarray profiles were generated for 28,671 maize cDNAs contained on gene chips SAM 1.1and SAM 3.0 (http://www.plantgenomics.iastate.edu/maizechip/). Two-condition experiment, rgd2 SAM vs non-mutant SAM cells. 6 Biological replicates with dye swap. One replicate per array.
2008-05-02 | E-GEOD-11325 | biostudies-arrayexpress
Project description:The recessive mutation ragged seedling2-R (rgd2-R) conditions defective lateral development of maize leaves. Although dorsiventral patterning is established in rgd2-R mutant leaves, some swapping of adaxial/abaxial epidermal identity may occur. Molecular analyses indicate that RGD2 is required for the coordination of dorsiventral and lateral patterning during maize leaf development, yet the RGD2 gene product and the mechanisms of RGD2 function are unknown. In order to investigate the genetic mechanisms downstream of RGD2 gene function, SAM-specific transcriptional profiling of rgd2-R is compared to that of nonmutant using laser microdissection microarray. Whole SAMs were laser-microdissected from rgd2-R mutant and non-mutant seedlings grown under the same controlled conditions. Microarray profiles were generated for 28,671 maize cDNAs contained on gene chips SAM 1.1and SAM 3.0 (http://www.plantgenomics.iastate.edu/maizechip/). Keywords: Genetic modification
2008-05-03 | GSE11325 | GEO
Project description:Little is known about transcriptional control of neurite branching or presynaptic differentiation, events that occur relatively late in neuronal development. Using the C. elegans mechanosensory circuit as an in vivo model, we show that SAM-10, an ortholog of mammalian Single-Stranded DNA binding Protein (SSDP), functions cell-autonomously in the nucleus to regulate synaptic differentiation as well as positioning of a single neurite branch. PLM mechanosensory neurons in sam-10 mutants exhibit abnormal placement of the neurite branch point, and defective synaptogenesis, characterized by an overextended synaptic varicosity, underdeveloped synaptic morphology and disrupted co-localization of active zone and synaptic vesicles. SAM-10 functions coordinately with LDB-1 (Lim Domain Binding protein-1), demonstrated by our observations that 1) mutations in either gene show similar defects in PLM neurons; and 2) LDB-1 is required for SAM-10 nuclear localization. SAM-10 regulates PLM synaptic differentiation by suppressing transcription of prk-2, which encodes an ortholog of the mammalian Pim kinase family. PRK-2-mediated activities of SAM-10 are specifically involved in PLM synaptic differentiation, but not other sam-10 phenotypes such as neurite branching. Thus, these data reveal a novel transcriptional signaling pathway that regulates neuronal specification of neurite branching and presynaptic differentiation.
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