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Synthetic lethality

Maciej Dylewski, Monika Ćwiklińska, Katarzyna Potrykus
Small RNA are very important post-transcriptional regulators in both, bacteria and eukaryotes. One of such sRNA is GraL, encoded in the greA leader region and conserved among enteric bacteria. Here, we conducted a bioinformatics search for GraL's targets in trans and validated our findings in vivo by constructing fusions of probable targets with lacZ and measuring their activity when GraL was overexpressed. Only one target's activity (nudE) decreased under those conditions and was thus selected for further analysis...
March 12, 2018: Acta Biochimica Polonica
John J Miles, Mai Ping Tan, Garry Dolton, Emily Sj Edwards, Sarah Ae Galloway, Bruno Laugel, Mathew Clement, Julia Makinde, Kristin Ladell, Katherine K Matthews, Thomas S Watkins, Katie Tungatt, Yide Wong, Han Siean Lee, Richard J Clark, Johanne M Pentier, Meriem Attaf, Anya Lissina, Ann Ager, Awen Gallimore, Pierre J Rizkallah, Stephanie Gras, Jamie Rossjohn, Scott R Burrows, David K Cole, David A Price, Andrew K Sewell
Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic "mimics" using subunits that do not exist in the natural world. We developed a platform based on D-amino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus...
March 12, 2018: Journal of Clinical Investigation
Hui Chen, Hudan Liu, Guoliang Qing
The MYC family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. Although Myc inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of Myc has been a challenge for decades owing to its "undruggable" protein structure...
2018: Signal Transduction and Targeted Therapy
Shu Shimada, Yoshimitsu Akiyama, Kaoru Mogushi, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Hiromi Nagasaki, Hiroshi Fukamachi, Yasuhito Yuasa, Shinji Tanaka
BACKGROUND: Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells. METHODS: We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents...
March 12, 2018: British Journal of Cancer
Piet A van Rijn, Mieke A Maris-Veldhuis, Christiaan A Potgieter, René G P van Gennip
African horse sickness virus (AHSV) is a virus species in the genus Orbivirus of the family Reoviridae. Currently, nine serotypes have been defined showing limited cross neutralization. AHSV is transmitted by species of Culicoides biting midges and causes African Horse Sickness (AHS) in equids with a mortality up to 95% in naïve domestic horses. AHS has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates are competent vectors of closely related bluetongue virus...
March 7, 2018: Vaccine
Ke Li, Huaying Yan, Wenhao Guo, Mei Tang, Xinyu Zhao, Aiping Tong, Yong Peng, Qintong Li, Zhu Yuan
PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects...
March 6, 2018: Experimental Cell Research
Jing Shen, Sara Najafi, Sina Stäble, Johannes Fabian, Emily Koeneke, Fiona R Kolbinger, Jagoda K Wrobel, Benjamin Meder, Martin Distel, Tino Heimburg, Wolfgang Sippl, Manfred Jung, Heike Peterziel, Dominique Kranz, Michael Boutros, Frank Westermann, Olaf Witt, Ina Oehme
The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene...
March 7, 2018: Cell Death and Differentiation
Enrico Mini, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, Stefania Nobili
The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil...
March 5, 2018: Oncology Research
Jianbiao Zhou, Sabrina Hui-Min Toh, Zit-Liang Chan, Jessie Yiying Quah, Jing-Yuan Chooi, Tuan Zea Tan, Phyllis S Y Chong, Qi Zeng, Wee-Joo Chng
BACKGROUND: Protein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor. METHODS: In this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients...
March 7, 2018: Journal of Hematology & Oncology
Kyung-Ho Roh, Hannah W Song, Pallab Pradhan, Kevin Bai, Caitlin D Bohannon, Gordon Dale, Jardin Leleux, Joshy Jacob, Krishnendu Roy
B cells play a major role in the adaptive immune response by producing antigen-specific antibodies against pathogens and imparting immunological memory. Following infection or vaccination, antibody-secreting B cells and memory B cells are generated in specialized regions of lymph nodes and spleens, called germinal centers. Here, we report a fully synthetic ex-vivo system that recapitulates the generation of antigen-specific germinal-center (GC) like B cells using material-surface driven polyvalent signaling...
February 21, 2018: Biomaterials
Christina Kratschmer, Matthew Levy
Pancreatic cancer is one of the most lethal malignancies. Treatment with the first-line agent, gemcitabine, is often unsuccessful because it, like other traditional chemotherapeutic agents, is non-specific, resulting in off-target effects that necessitate administration of subcurative doses. Alternatively, monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are highly toxic small molecules that require ligand-targeted delivery. MMAE has already received FDA approval as a component of an anti-CD30 antibody-drug conjugate, brentuximab vedotin...
March 2, 2018: Molecular Therapy. Nucleic Acids
Na Zhao, Jin Cao, Longyong Xu, Qianzi Tang, Lacey E Dobrolecki, Xiangdong Lv, Manisha Talukdar, Yang Lu, Xiaoran Wang, Dorothy Z Hu, Qing Shi, Yu Xiang, Yunfei Wang, Xia Liu, Wen Bu, Yi Jiang, Mingzhou Li, Yingyun Gong, Zheng Sun, Haoqiang Ying, Bo Yuan, Xia Lin, Xin-Hua Feng, Sean M Hartig, Feng Li, Haifa Shen, Yiwen Chen, Leng Han, Qingping Zeng, John B Patterson, Benny Abraham Kaipparettu, Nagireddy Putluri, Frank Sicheri, Jeffrey M Rosen, Michael T Lewis, Xi Chen
The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer...
February 26, 2018: Journal of Clinical Investigation
Filip Mundt, Sandeep Rajput, Shunqiang Li, Kelly V Ruggles, Arshag D Mooradian, Philipp Mertins, Michael A Gillette, Karsten Krug, Zhanfang Guo, Jeremy Hoog, Petra Erdmann-Gilmore, Tina Primeau, Shixia Huang, Dean P Edwards, Xiaowei Wang, Xuya Wang, Emily Kawaler, D R Mani, Karl R Clauser, Feng Gao, Jingqin Luo, Sherri R Davies, Gary L Johnson, Kuan-Lin Huang, Christopher J Yoon, Li Ding, David Fenyö, Matthew J Ellis, R Reid Townsend, Jason M Held, Steven A Carr, Cynthia X Ma
Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib...
February 22, 2018: Cancer Research
Dandan Li, Winifred Lo, Udo Rudloff
Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an estimated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer...
February 22, 2018: Clinical and Translational Medicine
Charlotte Pawlyn, Andrea Loehr, Cody Ashby, Ruslana Tytarenko, Shayu Deshpande, James Sun, Kyle Fedorchak, Tariq Mughal, Faith E Davies, Brian A Walker, Gareth J Morgan
PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Gertrud E Feiersinger, Kristina Trattnig, Peter D Leitner, Fabian Guggenberger, Alexander Oberhuber, Sarah Peer, Martin Hermann, Ira Skvortsova, Jana Vrbkova, Jan Bouchal, Zoran Culig, Frédéric R Santer
A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor Olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa we evaluated a potential use for Olaparib in combination with first-line endocrine treatments, androgen deprivation and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy...
February 21, 2018: Molecular Oncology
Robert D Morgan, Andrew R Clamp, D Gareth R Evans, Richard J Edmondson, Gordon C Jayson
PURPOSE: Poly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA damage repair deficiency and may induce cell death...
February 20, 2018: Cancer Chemotherapy and Pharmacology
John Smestad, Oksana Hamidi, Lin Wang, Molly Nelson Holte, Fatimah Al Khazal, Luke Erber, Yue Chen, L James Maher
Succinate dehydrogenase (SDH)-loss pheochromocytoma and paraganglioma (PPGL) are tumors driven by metabolic derangement. SDH loss leads to accumulation of intracellular succinate, which competitively inhibits dioxygenase enzymes, causing activation of pseudohypoxic signaling and hypermethylation of histones and DNA. The mechanisms by which these alterations lead to tumorigenesis are unclear, however. In an effort to fundamentally understand how SDH loss reprograms cell biology, we developed an immortalized mouse embryonic fibroblast cell line with conditional disruption of Sdhc and characterize the kinetics of Sdhc gene rearrangement, SDHC protein loss, succinate accumulation, and the resultant hypoproliferative phenotype...
January 19, 2018: Oncotarget
Paolo Gallipoli, George Giotopoulos, Konstantinos Tzelepis, Ana S H Costa, Shabana Vohra, Paula Medina-Perez, Faisal Basheer, Ludovica Marando, Lorena Di Lisio, Joao M L Dias, Haiyang Yun, Daniel Sasca, Sarah J Horton, George Vassiliou, Christian Frezza, Brian J P Huntly
FLT3 internal tandem duplication (FLT3ITD ) are common mutations in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide CRISPR/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment...
February 20, 2018: Blood
Masayuki Hashimoto, Hiroaki Matsushima, I Putu Suparthana, Hiroshi Ogasawara, Hiroki Yamamoto, ChingHao Teng, Junichi Sekiguchi
Bacterial cells are covered with peptidoglycan (PG) layer(s), serving as the cellular exoskeleton. The PG sacculus changes its shape during cell growth, and thus both the synthesis and disassembly of PG are important for cell proliferation. In Bacillus subtilis, four dl-endopeptidases (DLEPases; LytE, LytF, CwlO and CwlS) are involved in the maintenance of cell morphology. The lytE cwlO double mutant exhibits synthetic lethality and defective cell elongation, while the lytE lytF cwlS triple mutant exhibits defective cell separation, albeit with septum formation...
January 25, 2018: Microbiology
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