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Oncogene addiction

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https://www.readbyqxmd.com/read/28213330/drug-discovery-strategies-in-the-field-of-tumor-energy-metabolism-limitations-by-metabolic-flexibility-and-metabolic-resistance-to-chemotherapy
#1
REVIEW
N D Amoedo, E Obre, R Rossignol
The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28202458/sensitivity-to-pi3k-and-akt-inhibitors-is-mediated-by-divergent-molecular-mechanisms-in-subtypes-of-dlbcl
#2
Tabea Erdmann, Pavel Klener, James T Lynch, Michael Grau, Petra Vočková, Jan Molinsky, Diana Tuskova, Kevin Hudson, Urszula M Polanska, Michael Grondine, Michele Mayo, Beiying Dai, Matthias Pfeifer, Kristian Erdmann, Daniela Schwammbach, Myroslav Zapukhlyak, Annette M Staiger, German Ott, Wolfgang E Berdel, Barry R Davies, Francisco Cruzalegui, Marek Trneny, Peter Lenz, Simon T Barry, Georg Lenz
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype...
February 15, 2017: Blood
https://www.readbyqxmd.com/read/28182330/heat-shock-protein-27-hsp27-hspb1-is-synthetic-lethal-to-cells-with-oncogenic-activation-of-met-egfr-and-braf
#3
John David Konda, Martina Olivero, Daniele Musiani, Simona Lamba, Maria Flavia Di Renzo
The small Heat Shock Protein of 27 KDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumor behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene-addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET-addicted EBC-1 lung cancer cells, EGFR-addicted colorectal carcinoma DiFi cells and BRAF-addicted colorectal carcinoma COLO205 and OXCO-1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent...
February 9, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28158294/deep-proteome-mapping-of-wm-266-4-human-metastatic-melanoma-cells-from-oncogenic-addiction-to-druggable-targets
#4
Eumorphia G Konstantakou, Athanassios D Velentzas, Athanasios K Anagnostopoulos, Zoi I Litou, Ourania A Konstandi, Aikaterini F Giannopoulou, Ema Anastasiadou, Gerassimos E Voutsinas, George Th Tsangaris, Dimitrios J Stravopodis
Cutaneous melanoma is a malignant tumor of skin melanocytes that are pigment-producing cells located in the basal layer (stratum basale) of epidermis. Accumulation of genetic mutations within their oncogenes or tumor-suppressor genes compels melanocytes to aberrant proliferation and spread to distant organs of the body, thereby resulting in severe and/or lethal malignancy. Metastatic melanoma's heavy mutational load, molecular heterogeneity and resistance to therapy necessitate the development of novel biomarkers and drug-based protocols that target key proteins involved in perpetuation of the disease...
2017: PloS One
https://www.readbyqxmd.com/read/28153089/genome-editing-reveals-glioblastoma-addiction-to-microrna-10b
#5
Rachid El Fatimy, Shruthi Subramanian, Erik J Uhlmann, Anna M Krichevsky
Glioblastoma (GBM) brain tumor remains among the most lethal and incurable human diseases. Oncogenic microRNA-10b (miR-10b) is strongly and universally upregulated in GBM, and its inhibition by antisense oligonucleotides (ASOs) reduces the growth of heterogeneous glioma cells; therefore, miR-10b represents a unique therapeutic target for GBM. Here we explored the effects of miR-10b gene editing on GBM. Using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system, we investigated effects of miR-10b gene editing on the growth of cultured human glioma cells, tumor-initiating stem-like cells, and mouse GBM xenografts, as well as the oncogene-induced transformation of normal astrocytes...
February 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28118080/oncogene-dependent-requirement-of-fatty-acid-synthase-in-hepatocellular-carcinoma
#6
Li Che, Maria G Pilo, Antonio Cigliano, Gavinella Latte, Maria M Simile, Silvia Ribback, Frank Dombrowski, Matthias Evert, Xin Chen, Diego F Calvisi
Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery...
January 24, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28117670/exploring-the-ck2-paradox-restless-dangerous-dispensable
#7
REVIEW
Cinzia Franchin, Christian Borgo, Silvia Zaramella, Luca Cesaro, Giorgio Arrigoni, Mauro Salvi, Lorenzo A Pinna
The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its "lateral" implication in a variety of signaling pathways is now soundly documented...
January 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28104295/systematic-drug-sensitivity-testing-reveals-synergistic-growth-inhibition-by-dasatinib-or-mtor-inhibitors-with-paclitaxel-in-ovarian-granulosa-cell-tumor-cells
#8
Ulla-Maija Haltia, Noora Andersson, Bhagwan Yadav, Anniina Färkkilä, Evgeny Kulesskiy, Matti Kankainen, Jing Tang, Ralf Bützow, Annika Riska, Arto Leminen, Markku Heikinheimo, Olli Kallioniemi, Leila Unkila-Kallio, Krister Wennerberg, Tero Aittokallio, Mikko Anttonen
OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing...
January 16, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28067062/developments-in-pharmacotherapy-for-treating-metastatic-non-small-cell-lung-cancer
#9
Antonio Rossi, Paola Claudia Sacco, Giuseppe Santabarbara, Assunta Sgambato, Francesca Casaluce, Giovanni Palazzolo, Paolo Maione, Cesare Gridelli
Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available. Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards...
February 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28065413/therapeutic-targeting-of-mll-degradation-pathways-in-mll-rearranged-leukemia
#10
Kaiwei Liang, Andrew G Volk, Jeffrey S Haug, Stacy A Marshall, Ashley R Woodfin, Elizabeth T Bartom, Joshua M Gilmore, Laurence Florens, Michael P Washburn, Kelly D Sullivan, Joaquin M Espinosa, Joseph Cannova, Jiwang Zhang, Edwin R Smith, John D Crispino, Ali Shilatifard
Chromosomal translocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressive leukemia with dismal outcomes. Despite similar expression at the mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable. We report that UBE2O functions in regulating the stability of wild-type MLL in response to interleukin-1 signaling. Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elongation complex...
January 12, 2017: Cell
https://www.readbyqxmd.com/read/28035683/nuclear-inclusion-bodies-of-mutant-and-wild-type-p53-in-cancer-a-hallmark-of-p53-inactivation-and-proteostasis-remodeling-by-p53-aggregation
#11
Frederik De Smet, Mirian Saiz Rubio, Daphne Hompes, Evelyne Naus, Greet De Baets, Tobias Langenberg, Mark S Hipp, Bert Houben, Filip Claes, Sarah Charbonneau, Javier Delgado Blanco, Stephane Plaisance, Shakti Ramkissoon, Lori Ramkissoon, Colinda Simons, Piet van den Brandt, Matty Weijenberg, Manon Van England, Sandrina Lambrechts, Frederic Amant, André D'Hoore, Keith L Ligon, Xavier Sagaert, Joost Schymkowitz, Frederic Rousseau
Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders...
December 30, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/28028233/aberrantly-expressed-lgr4-empowers-wnt-signaling-in-multiple-myeloma-by-hijacking-osteoblast-derived-r-spondins
#12
Harmen van Andel, Zemin Ren, Iris Koopmans, Sander P J Joosten, Kinga A Kocemba, Wim de Lau, Marie José Kersten, Alexander M de Bruin, Jeroen E J Guikema, Hans Clevers, Marcel Spaargaren, Steven T Pals
The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27994142/regulatory-module-involving-fgf13-mir-504-and-p53-regulates-ribosomal-biogenesis-and-supports-cancer-cell-survival
#13
Débora R Bublik, Slađana Bursać, Michal Sheffer, Ines Oršolić, Tali Shalit, Ohad Tarcic, Eran Kotler, Odelia Mouhadeb, Yonit Hoffman, Gilad Fuchs, Yishai Levin, Siniša Volarević, Moshe Oren
The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27993682/trastuzumab-stimulation-of-ribosomal-protein-s6-kinase-1-s6k1-predicts-de-novo-trastuzumab-resistance
#14
Felicia C Huynh, Daniel Nguyen, Frank E Jones
Breast cancer is a complex disease with at least five different molecular subtypes identified. The breast tumor molecular subtypes guide stratification of patients for specific targeted therapy regimens and each subtype is associated with significantly different patient outcomes. For example, patients with the HER2 positive molecular subtype benefit from the HER2 targeted therapy trastuzumab. Unfortunately, women with the HER2 positive molecular subtype have the worst overall prognosis and nearly 70% of women with HER2 positive breast cancer exhibit de novo or acquired resistance to trastuzumab...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27991934/ras-oncogene-independent-activation-of-ralb-signaling-is-a-targetable-mechanism-of-escape-from-nras-v12-oncogene-addiction-in-acute-myeloid-leukemia
#15
E J Pomeroy, L A Lee, R D W Lee, D K Schirm, N A Temiz, J Ma, T A Gruber, E Diaz-Flores, B S Moriarity, J R Downing, K M Shannon, D A Largaespada, C E Eckfeldt
Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27988359/targeting-amino-acid-metabolism-for-cancer-therapy
#16
REVIEW
Michael J Lukey, William P Katt, Richard A Cerione
To support sustained biomass accumulation, tumor cells undergo metabolic reprogramming. Nutrient transporters and metabolic enzymes are regulated by the same oncogenic signals that drive cell-cycle progression. Some of the earliest cancer therapies used antimetabolites to disrupt tumor metabolism, and there is now renewed interest in developing drugs that target metabolic dependencies. Many cancers exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis...
December 14, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27941351/anti-cancer-effect-of-cap-translation-inhibitor-4egi-1-in-human-glioma-u87-cells-involvement-of-mitochondrial-dysfunction-and-er-stress
#17
Ming Wu, Chi Zhang, Xue-Jun Li, Qing Liu, Siyi Wanggou
BACKGROUND: Cancer cells are frequently addicted to deregulated oncogenic protein translation that usually arises as a consequence of increased signaling flux from eIF4F activation. The small molecule 4EG-I, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anticancer effects in animal models of human cancers. METHODS: Here, we extensively investigated the anticancer activity of 4EGI-1 in human glioma U87 cells...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27912893/-perioperative-therapies-in-surgical-non-n2%C3%A2-non-small-cell-lung-cancer
#18
REVIEW
Anne-Marie Ruppert, Armelle Lavolé, Jalal Assouad, Jacques Cadranel, Marie Wislez
Platinum-based perioperative chemotherapy is actually the standard of care in stage II-IIIa non-small cell lung cancer (NSCLC). A benefit may also be seen in stage IB NSCLC with tumors of more than 4cm of diameter. Perioperative chemotherapy improves 5-year survival of 4 to 15%. This benefit is mainly proved by postoperative chemotherapy trials. Nevertheless, preoperative chemotherapy has advantages: a better tolerance, an estimation of tumor chemosensibility, without an increased postoperative morbimortality...
January 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/27912827/new-targets-in-non-small-cell-lung-cancer
#19
REVIEW
Soo J Park, Soham More, Ayesha Murtuza, Brian D Woodward, Hatim Husain
With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27876887/high-energy-particle-radiation-associated-oncogenic-transformation-in-normal-mice-insight-into-the-connection-between-activation-of-oncotargets-and-oncogene-addiction
#20
Natarajan Aravindan, Sheeja Aravindan, Krishnan Manickam, Mohan Natarajan
Concerns on high-energy particle radiation-induced tumorigenic transformation of normal tissue in astronauts, and in cancer patients undergoing radiotherapy, emphasizes the significance of elucidating the mechanisms involved in radiogenic transformation processes. Mostly used genetically modified or tumor-prone models are less reliable in determining human health risk in space or protracted post-treatment normal tissue toxicity. Here, in wild type C57BL/6 mice, we related the deregulation of distinctive set of tissue-specific oncotargets in major organs upon (56)Fe (600 MeV/amu; 0...
November 23, 2016: Scientific Reports
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