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Synthetic lethality

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https://www.readbyqxmd.com/read/28923231/future-clinical-trials-genetically-driven-trials
#1
REVIEW
Igor Astsaturov
The design of modern oncology clinical trials seeks to match patients' cancer molecular biomarkers with medications that specifically target those biomarkers, a general paradigm shift in cancer care coined clinical cancer biology. This approach exploits the synthetic lethality between a specific genetic alteration in the cancer cell and a drug: rapid termination of exaggerated kinase activity exemplifies this phenomenon. Synthetic lethality-based investigations are driven by rapidly evolving technologies for cancer molecular profiling...
October 2017: Surgical Oncology Clinics of North America
https://www.readbyqxmd.com/read/28922373/dynein-light-chain-regulates-adaptive-and-innate-b-cell-development-by-distinctive-genetic-mechanisms
#2
Ashleigh King, Lingli Li, David M Wong, Rui Liu, Rebecca Bamford, Andreas Strasser, David M Tarlinton, Jörg Heierhorst
Mechanistic differences in the development and function of adaptive, high-affinity antibody-producing B-2 cells and innate-like, "natural" antibody-producing B-1a cells remain poorly understood. Here we show that the multi-functional dynein light chain (DYNLL1/LC8) plays important roles in the establishment of B-1a cells in the peritoneal cavity and in the ongoing development of B-2 lymphoid cells in the bone marrow of mice. Epistasis analyses indicate that Dynll1 regulates B-1a and early B-2 cell development in a single, linear pathway with its direct transcriptional activator ASCIZ (ATMIN/ZNF822), and that the two genes also have complementary functions during late B-2 cell development...
September 18, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28914618/hereditary-breast-and-ovarian-cancer-syndrome-moving-beyond-brca1-and-brca2
#3
Lien N Hoang, Blake C Gilks
The recent implementation of next generation sequencing and multigene platforms has expanded the spectrum of hereditary breast and ovarian cancer syndrome, beyond the traditional genes BRCA1 and BRCA2. A large number of other moderate penetrance genes have now been uncovered, which also play critical roles in repairing double stranded DNA breaks through the homologous recombination pathway. This review discusses the landmark discoveries of BRCA1 and BRCA2, the homologous repair pathway and new genes discovered in hereditary breast and ovarian cancer syndrome, as well as their clinicopathologic significance and implications for genetic testing...
September 13, 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/28912598/synthetic-lethality-screens-point-the-way-to-new-cancer-drug-targets
#4
Asher Mullard
No abstract text is available yet for this article.
September 15, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28899698/betulinic-acid-derivative-ba5-a-dual-nf-kb-calcineurin-inhibitor-alleviates-experimental-shock-and-delayed-hypersensitivity
#5
Cássio Santana Meira, Renan Fernandes do Espírito Santo, Tatiana Barbosa Dos Santos, Iasmim Diniz Orge, Dahara Keyse Carvalho Silva, Elisalva Teixeira Guimarães, Luciana Souza de Aragão França, José Maria Barbosa-Filho, Diogo Rodrigo Magalhães Moreira, Milena Botelho Pereira Soares
Betulinic acid (BA) is a naturally occurring triterpenoid with several biological properties already described, including immunomodulatory activity. Here we investigated the immunomodulatory activity of eight semi-synthetic amide derivatives of betulinic acid. Screening of derivatives BA1-BA8 led to the identification of compounds with superior immunomodulatory activity than BA on activated macrophages and lymphocytes. BA5, the most potent derivative, inhibited nitric oxide and TNFα production in a concentration-dependent manner, and decreased NF-κB activation in Raw 264...
September 9, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28893618/lenalidomide-modulates-gene-expression-in-human-abc-dlbcl-cells-by-regulating-ikaros-interaction-with-an-intronic-control-region-of-spib
#6
Lauren A Solomon, Carolina R Batista, Rodney P DeKoter
Activated B cell diffuse large B cell lymphoma (ABC-DLBCL) has poor prognosis compared to other DLBCL types, and therefore represents a top priority for developing novel therapies. Lenalidomide, an immunomodulatory drug in trials for treatment of ABC-DLBCL, targets the transcription factor IKAROS for degradation by the Cereblon E3 ubiquitin ligase complex. In this study, we determined whether the gene encoding the transcription factor SPI-B is a target of IKAROS. Using cultured ABC-DLBCL cell lines, we found that high levels of SPI-B expression conferred resistance to lenalidomide...
September 8, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28890093/mechanistic-and-fc-requirements-for-inhibition-of-sudan-virus-entry-and-in-vivo-protection-by-a-synthetic-antibody
#7
Daniel Hofmann, Samantha E Zak, Elisabeth K Nyakatura, Eva Mittler, Russell R Bakken, Kartik Chandran, John M Dye, Jonathan R Lai
The Sudan virus (SUDV), an ebolavirus, causes severe hemorrhagic fever with human case fatality rates of ∼50%. Previous work from our lab demonstrated the synthetic antibody F4 potently inhibits viral entry and protects against lethal virus challenge in mice [Chen et al., ACS Chem. Biol., 2014, 9, 2263-2273]. Here, we explore mechanistic requirements as well as contribution of the Fc region and function on neutralization and in vivo protection. Live cell imaging demonstrates that the antibody colocalizes with vesicular stomatitis virus particles containing the Sudan virus glycoprotein (VSV-GPSUDV) and that the antibody is rapidly degraded within cellular endosomes...
September 8, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28883017/nf%C3%AE%C2%BAb-signaling-in-alveolar-rhabdomyosarcoma
#8
Megan M Cleary, Atiya Mansoor, Teagan Settelmeyer, Yuichi Ijiri, Katherine J Ladner, Matthew N Svalina, Brian P Rubin, Denis C Guttridge, Charles Keller
Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB-YY1-miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways...
September 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28882690/toxicogenomic-and-bioinformatics-platforms-to-identify-key-molecular-mechanisms-of-a-curcumin-analogue-dm-1-toxicity-in-melanoma-cells
#9
Érica Aparecida de Oliveira, Diogenes Saulo de Lima, Lucas Esteves Cardozo, Garcia Ferreira de Souza, Nayane de Souza, Debora Kristina Alves-Fernandes, Fernanda Faião-Flores, José Agustín Pablo Quincoces, Silvia Berlanga de Moraes Barros, Helder I Nakaya, Gisele Monteiro, Silvya Stuchi Maria-Engler
Melanoma is a highly invasive and metastatic cancer with high mortality rates and chemoresistance. Around 50% of melanomas are driven by activating mutations in BRAF that has led to the development of potent anti-BRAF inhibitors. However resistance to anti-BRAF therapy usually develops within a few months and consequently there is a need to identify alternative therapies that will bypass BRAF inhibitor resistance. The curcumin analogue DM-1 (sodium 4-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) has substantial anti-tumor activity in melanoma, but its mechanism of action remains unclear...
September 4, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28881566/ppars-as-determinants-of-the-estrogen-receptor-lineage-use-of-synthetic-lethality-for-the-treatment-of-estrogen-receptor-negative-breast-cancer
#10
Robert I Glazer, Levy Kopelovich
THE DILEMMA: Estrogen receptora-negative (ER-) breast cancer lacks a specific critical target to control tumor progression. THE OBJECTIVE: To identify mechanisms that enable increased expression of the ER+ lineage in an otherwise ER- breast cancer. PREFACE: The nuclear receptor superfamily members PPARγ and PPARδ regulate gene expression associated with a multitude of pathways, including intermediary metabolism, angiogenesis, proliferation and inflammation (see reviews [1-3])...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880543/the-transition-state-structure-for-human-mat2a-from-isotope-effects
#11
Ross S Firestone, Vern L Schramm
Human methionine S-adenosyltransferase (MAT2A) catalyzes the formation of S-adenosylmethionine (SAM) from ATP and methionine. Synthetic lethal genetic analysis has identified MAT2A as an anticancer target in tumor cells lacking expression of 5'-methylthioadenosine phosphorylase (MTAP). Approximately 15% of human cancers are MTAP(-/-). The remainder can be rendered MTAP(-) through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (Cf), and binding isotope effect (BIE) measurements combined with quantum mechanical (QM) calculations to solve the transition state structure of human MAT2A...
September 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28878380/an-in-silico-approach-to-predict-and-exploit-synthetic-lethality-in-cancer-metabolism
#12
Iñigo Apaolaza, Edurne San José-Eneriz, Luis Tobalina, Estíbaliz Miranda, Leire Garate, Xabier Agirre, Felipe Prósper, Francisco J Planes
Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28871247/archaeal-persisters-persister-cell-formation-as-a-stress-response-in-haloferax-volcanii
#13
Julianne Megaw, Brendan F Gilmore
Persister cells are phenotypic variants within a microbial population, which are dormant and transiently tolerant to stress. Persistence has been studied extensively in bacteria, and in eukaryotes to a limited extent, however, it has never been observed in archaea. Using the model haloarchaeon, Haloferax volcanii DS2, we demonstrated persister cell formation in this domain, with time-kill curves exhibiting a characteristic biphasic pattern following starvation or exposure to lethal concentrations of various biocidal compounds...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28866094/palbociclib-a-selective-cdk4-6-inhibitor-enhances-the-effect-of-selumetinib-in-ras-driven-non-small-cell-lung-cancer
#14
Jianya Zhou, Shumeng Zhang, Xi Chen, Xianan Zheng, Yinan Yao, Guohua Lu, Jianying Zhou
KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A...
September 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28860588/synthetic-lethality-screens-point-the-way-to-new-cancer-drug-targets
#15
Asher Mullard
No abstract text is available yet for this article.
September 1, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28851861/synthetic-lethality-between-androgen-receptor-signalling-and-the-parp-pathway-in-prostate-cancer
#16
Mohammad Asim, Firas Tarish, Heather I Zecchini, Kumar Sanjiv, Eleni Gelali, Charles E Massie, Ajoeb Baridi, Anne Y Warren, Wanfeng Zhao, Christoph Ogris, Leigh-Anne McDuffus, Patrice Mascalchi, Greg Shaw, Harveer Dev, Karan Wadhwa, Paul Wijnhoven, Josep V Forment, Scott R Lyons, Andy G Lynch, Cormac O'Neill, Vincent R Zecchini, Paul S Rennie, Aria Baniahmad, Simon Tavaré, Ian G Mills, Yaron Galanty, Nicola Crosetto, Niklas Schultz, David Neal, Thomas Helleday
Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo...
August 29, 2017: Nature Communications
https://www.readbyqxmd.com/read/28842874/transposon-insertion-site-sequencing-for-synthetic-lethal-screening
#17
Yoshiharu Yamaichi, Tobias Dörr
Transposon insertion site sequencing (TIS) permits genome-wide, quantitative fitness assessment of individual genomic loci. In addition to the identification of essential genes in given growth conditions, TIS enables the elucidation of genetic networks such as synthetic lethal or suppressor gene combinations. Therefore, TIS becomes an exceptionally powerful tool for the high-throughput determination of genotype-phenotype relationships in bacteria. Here, we describe a protocol for the generation of high-density transposon insertion libraries and subsequent preparation of DNA samples for Illumina sequencing using the Gram-negative bacterium Vibrio cholerae as an example...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28841282/synthetic-lethality-triggered-by-combining-olaparib-with-brca2-rad51-disruptors
#18
Federico Falchi, Elisa Giacomini, Tiziana Masini, Nicolas Boutard, Lorenza Di Ianni, Marcella Manerba, Fulvia Farabegoli, Lara Rossini, Janet Robertson, Saverio Minucci, Isabella Pallavicini, Giuseppina Di Stefano, Marinella Roberti, Roberto Pellicciari, Andrea Cavalli
In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways...
September 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28840549/approaches-for-identifying-novel-targets-in-precision-medicine-lessons-from-dna-repair
#19
Dean T Williams, Christopher J Staples
Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplified by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the first 'synthetic lethal' medicine for patients with BRCA-mutant cancers...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28839115/genome-scale-genetic-interactions-and-cell-imaging-confirm-cytokinesis-as-deleterious-to-transient-topoisomerase-ii-deficiency-in-saccharomyces-cerevisiae
#20
Cristina Ramos-Pérez, Jessel Ayra-Plasencia, Emiliano Matos-Perdomo, Michael Lisby, Grant W Brown, Félix Machín
Topoisomerase II (Top2) is the essential protein that resolves DNA catenations. When Top2 is inactivated, mitotic catastrophe results from massive entanglement of chromosomes. Top2 is also the target of many first-line anticancer drugs, the so-called Top2 poisons. Often, tumors become resistant to these drugs by acquiring hypomorphic mutations in the genes encoding Top2. Here, we have compared the cell cycle and nuclear segregation of two coisogenic Saccharomyces cerevisiae strains carrying top2 thermosensitive alleles that differ in their resistance to Top2 poisons: the broadly-used poison-sensitive top2-4 and the poison-resistant top2-5 Furthermore, we have performed genome-scale Synthetic Genetic Array (SGA) analyses for both alleles under permissive conditions, chronic sublethal Top2 downregulation and acute, yet transient, Top2 inactivation...
August 24, 2017: G3: Genes—Genomes—Genetics
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