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Oncogene addiction

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https://www.readbyqxmd.com/read/28918056/the-therapeutic-potential-of-crispr-cas9-systems-in-oncogene-addicted-cancer-types-virally-driven-cancers-as-a-model-system
#1
REVIEW
Luqman Jubair, Nigel A J McMillan
The field of gene editing is undergoing unprecedented growth. The first ex vivo human clinical trial in China started in 2016, more than 1000 US patents have been filed, and there is exponential growth in publications. The ability to edit genes with high fidelity is promising for the development of new treatments for a range of diseases, particularly inherited conditions, infectious diseases, and cancers. For cancer, a major issue is the identification of driver mutations and oncogenes to target for therapeutic effect, and this requires the development of robust models with which to prove their efficacy...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28898697/chronic-cigarette-smoke-induced-epigenomic-changes-precede-sensitization-of-bronchial-epithelial-cells-to-single-step-transformation-by-kras-mutations
#2
Michelle Vaz, Stephen Y Hwang, Ioannis Kagiampakis, Jillian Phallen, Ashwini Patil, Heather M O'Hagan, Lauren Murphy, Cynthia A Zahnow, Edward Gabrielson, Victor E Velculescu, Hariharan P Easwaran, Stephen B Baylin
We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer...
September 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28893801/galectin-3-a-druggable-vulnerability-for-kras-addicted-cancers
#3
Laetitia Seguin, Maria F Camargo, Hiromi I Wettersten, Shumei Kato, Jay S Desgrosellier, Tami von Schalscha, Kathryn C Elliott, Erika Cosset, Jacqueline Lesperance, Sara M Weis, David A Cheresh
Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein Galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, Galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance...
September 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28881369/-molecular-pathogenesis-of-thyroid-nodules-relevance-for-clinical-care
#4
D Führer, T Musholt, K W Schmid
Thyroid nodules represent heterogeneous tumors with distinct molecular signatures. While benign thyroid nodules correspond to poly- or monoclonal tumors, thyroid carcinomas are monoclonal and thus "real" neoplasms. These are caused by somatic mutations that lead to the constitutive activation of specific signaling cascades and determine the corresponding histology and also partly the functional phenotype of the thyroid tumor. Dedifferentiation of thyroid carcinomas is accompanied by the occurrence of additional mutations in the tumors...
September 2017: Laryngo- Rhino- Otologie
https://www.readbyqxmd.com/read/28869494/-dicing-and-splicing-sphingosine-kinase-and-relevance-to-cancer
#5
REVIEW
Nahal Haddadi, Yiguang Lin, Ann M Simpson, Najah T Nassif, Eileen M McGowan
Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological diversity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper-SphK signaling) or "non-oncogenic addiction"...
September 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28843992/tracking-met-de-addiction-in-lung-cancer-a-road-towards-the-oncogenic-target
#6
REVIEW
S Pilotto, L Carbognin, N Karachaliou, P C Ma, R Rosell, G Tortora, E Bria
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype...
August 20, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28843358/brief-report-baseline-and-on-treatment-characteristics-of-serum-tumor-markers-in-stage-iv-oncogene-addicted-adenocarcinoma-of-the-lung
#7
Sinead A Noonan, Tejas Patil, Dexiang Gao, Gentry G King, Jessica R Thibault, Xian Lu, Paul A Bunn, Robert C Doebele, W Thomas Purcell, Anna E Barón, D Ross Camidge
INTRODUCTION: The role of serum tumor markers in the modern management of advanced non-small cell lung cancer remains poorly described. METHODS: A single center retrospective analysis of available CEA, CA125, CA19.9 and CA27.29 levels at baseline and on treatment in stage IV lung adenocarcinoma by oncogenic driver was conducted. RESULTS: 142 patients were analyzed (ALK=60, EGFR=50, ROS1=4 and KRAS=28). 82% of patients had at least one marker; 95% if all four markers measured (CA27...
August 23, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28833076/the-immune-system-prevents-recurrence-of-transplanted-but-not-autochthonous-antigenic-tumors-after-oncogene-inactivation-therapy
#8
Kathleen Anders, Olivia Kershaw, Lionel Larue, Achim D Gruber, Thomas Blankenstein
Targeted oncogene inactivation by small molecule inhibitors can be very effective but tumor recurrence is a frequent problem in the clinic. Therapy by inactivation of the cancer-driving oncogene in transplanted tumors was shown to be augmented in the presence of T cells. However, these experiments did not take into account the long-term, usually tolerogenic, interaction of de novo malignancies with the immune system. Here, we employed mice, in which SV40 large T (Tag) and firefly luciferase (Luc) as fusion protein (TagLuc) could be regulated with the Tet-on system and upon activation resulted in tumors after a long latency...
August 22, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28798902/the-mitochondrial-unfolded-protein-response-as-a-non-oncogene-addiction-to-support-adaptation-to-stress-during-transformation-in-cancer-and-beyond
#9
REVIEW
Timothy C Kenny, Giovanni Manfredi, Doris Germain
Upon accumulation of misfolded proteins in the mitochondria, the mitochondrial unfolded protein response (UPR(mt)) is activated. This review focuses on the role of this response in cancer. We discuss evidence that during transformation, the UPR(mt) may play an essential role in the maintenance of the integrity of the mitochondria in the face of increased oxidative stress. However, the role of the UPR(mt) in other diseases is also emerging and is therefore also briefly discussed.
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28775144/a-bifunctional-mapk-pi3k-antagonist-for-inhibition-of-tumor-growth-and-metastasis
#10
Stefanie Galbán, April A Apfelbaum, Carlos Espinoza, Kevin Heist, Henry Haley, Karan Bedi, Mats Ljungman, Craig J Galbán, Gary D Luker, Marcian Van Dort, Brian D Ross
Responses to targeted therapies frequently are brief with patients relapsing with drug resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS or BRAF addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN mutant melanomas...
August 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28772011/brain-molecular-changes-and-behavioral-alterations-induced-by-propofol-anesthesia-exposure-in-peripubertal-rats
#11
Željko Pavković, Kosara Smiljanić, Selma Kanazir, Desanka Milanović, Vesna Pešić, Sabera Ruždijić
BACKGROUND: Propofol is commonly used in modern anesthesiology. Some findings suggest that it is highly addictive. AIM: In this study it was examined whether propofol anesthesia exposure was able to induce behavioral alterations and brain molecular changes already described in addictive drug usage in peripubertal rats, during the onset of mid/periadolescence as a developmental period with increasing vulnerability to drug addiction. METHODS: The expression of D1 dopamine receptor, a dopamine, and cAMP-regulated phosphoprotein with a Mr 32 000; Ca(2+) /calmodulin-dependent protein kinase IIα; and Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog-B was examined in peripubertal rats 4, 24, and 48 hour after propofol anesthesia exposure by Western blot and immunohistochemistry...
September 2017: Paediatric Anaesthesia
https://www.readbyqxmd.com/read/28725634/ip3-receptor-mediated-calcium-signaling-and-its-role-in-autophagy-in-cancer
#12
REVIEW
Elzbieta Kania, Gemma Roest, Tim Vervliet, Jan B Parys, Geert Bultynck
Calcium ions (Ca(2+)) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca(2+) is shuffled between the cytoplasm and the major Ca(2+) stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca(2+) signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca(2+)-release channels in the ER. IP3Rs can transfer Ca(2+) to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28718439/super-enhancer-driven-transcriptional-dependencies-in-cancer
#13
Satyaki Sengupta, Rani E George
Transcriptional deregulation is one of the core tenets of cancer biology and is underpinned by alterations in both protein-coding genes and noncoding regulatory elements. Large regulatory elements, so-called super-enhancers (SEs), are central to the maintenance of cancer cell identity and promote oncogenic transcription to which cancer cells become highly addicted. Such dependence on SE-driven transcription for proliferation and survival offers an Achilles heel for the therapeutic targeting of cancer cells...
April 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28717217/tki-addicted-ros1-rearranged-cells-are-destined-to-survival-or-death-by-the-intensity-of-ros1-kinase-activity
#14
Hayato Ogura, Yuka Nagatake-Kobayashi, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
ROS1 rearrangement is observed in 1-2% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in ROS1-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation-mediated crizotinib-resistance in ROS1-fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by N-ethyl-N-nitrosourea mutagenesis screening using CD74-ROS1-expressing Ba/F3 cells...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28714957/il-11-contribution-to-tumorigenesis-in-an-nrf2-addiction-cancer-model
#15
H Kitamura, Y Onodera, S Murakami, T Suzuki, H Motohashi
The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers...
July 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28675450/synthetic-essentiality-targeting-tumor-suppressor-deficiencies-in-cancer
#16
REVIEW
Di Zhao, Ronald A DePinho
In this review, we summarize recent work exploring a novel conceptual approach termed "synthetic essentiality" as a means for targeting specific tumor suppressor gene deficiencies in cancer. With the aid of extensive publically available cancer genome and clinical databases, "synthetic essentiality" could be utilized to identify synthetic essential genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency. Synthetic essentiality expands the existing concepts for therapeutic strategies, including oncogene addiction, tumor maintenance, synthetic, and collateral lethality, to provide a framework for the discovery of cancer-specific vulnerabilities...
August 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28656876/co-dependency-between-kras-addiction-and-arhgef2-promotes-an-adaptive-escape-from-mapk-pathway-inhibition
#17
Oliver A Kent, Maria-Jose Sandi, Robert Rottapel
Oncogenic KRAS engages multiple effector pathways including the MAPK cascade to promote proliferation and survival of pancreatic cancer cells. KRAS-transformed cancer cells exhibit oncogene addiction to sustained activity of RAS for maintenance of malignant phenotypes. Previously, we have shown an essential role for the RHO guanine exchange factor ARHGEF2 for growth and survival of RAS-transformed pancreatic tumors. Here, we have determined that pancreatic cancer cells demonstrating KRAS addiction are significantly dependent on expression of ARHGEF2...
June 28, 2017: Small GTPases
https://www.readbyqxmd.com/read/28644754/expression-of-enzymes-related-to-glucose-metabolism-in-non-small-cell-lung-cancer-and-prognosis
#18
Alexandra Giatromanolaki, Efthimios Sivridis, Stella Arelaki, Michael I Koukourakis
Purpose/Aim: Cancer cells are addicted to glycolytic anaerobic pathways, in presence or in absence of a functional Krebs' cycle (phenomenon Warburg). This metabolic predilection relies on both extracellular (impaired vascularization and oxygenation) and intracellular (oncogenic activation of genes) causes. MATERIALS AND METHODS: We investigated the expression and prognostic relevance of enzymes involved in the glucose absorption and metabolism, monocarboxylate transporter (MCT) expression, MCT1 and MCT2, pentose pathway (Glucose-6-phospahte dehydrogenase G6PD), glycogene synthesis (glycogene synthase GYS1), glycolysis (Hexokinase HXKII, phosphofructokinase PFK1, fructose biphosphate aldolase), fate of pyruvate (pyruvate dehydrogenase PDH, phosphorylated pPDH, PDH kinase PDK1, lactate dehydrogenase LDH5 and LDH1) and key Kreb's cycle enzymes (citrate synthase CSynth and isocitrate dehydrogenase IDH)...
June 23, 2017: Experimental Lung Research
https://www.readbyqxmd.com/read/28640835/bilateral-blockade-of-mek-and-pi3k-mediated-pathways-downstream-of-mutant-kras-as-a-treatment-approach-for-peritoneal-mucinous-malignancies
#19
Murali R Kuracha, Peter Thomas, Brian W Loggie, Venkatesh Govindarajan
Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28523248/the-keap1-nrf2-system-in-cancer
#20
REVIEW
Keiko Taguchi, Masayuki Yamamoto
Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2...
2017: Frontiers in Oncology
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