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Oncogene addiction

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https://www.readbyqxmd.com/read/28067062/developments-in-pharmacotherapy-for-treating-metastatic-non-small-cell-lung-cancer
#1
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...
January 8, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28065413/therapeutic-targeting-of-mll-degradation-pathways-in-mll-rearranged-leukemia
#2
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
#3
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
#4
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...
December 27, 2016: 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
#5
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...
December 19, 2016: 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
#6
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...
December 18, 2016: 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
#7
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
#8
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
#9
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
#10
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...
November 29, 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/27912827/new-targets-in-non-small-cell-lung-cancer
#11
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
#12
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
https://www.readbyqxmd.com/read/27875549/the-synthetic-%C3%AE-nitrostyrene-derivative-cyt-rx20-inhibits-esophageal-tumor-growth-and-metastasis-via-pi3k-akt-and-stat3-pathways
#13
Wen-Chin Chiu, Yi-Chen Lee, Yu-Han Su, Yen-Yun Wang, Chun-Hao Tsai, Yi-An Hou, Chie-Hong Wang, Ying-Fong Huang, Chih-Jen Huang, Shah-Hwa Chou, Pei-Wen Hsieh, Shyng-Shiou F Yuan
The β-nitrostyrene family have been implicated for anti-cancer property. However, the pharmacological role of β-nitrostyrene in esophageal cancer remain unclear. Here, a β-nitrostyrene derivative, CYT-Rx20, was synthesized and assessed for its anti-cancer activities and underlying mechanism in esophageal cancer. CYT-Rx20 induced cytotoxicity in esophageal cancer cells by promoting apoptosis through activation of caspase cascade and poly(ADP-ribose) polymerase (PARP) cleavage. Besides, CYT-Rx20 inhibited esophageal cancer cell migration and invasion by regulating the expression of epithelial to mesenchymal transition (EMT) markers...
2016: PloS One
https://www.readbyqxmd.com/read/27872099/conflicting-signals-for-cancer-treatment
#14
Pierre Sujobert, Alain Trautmann
Next-generation sequencing technologies have provided us with a precise description of the mutational burden of cancers, making it possible to identify targetable oncogene addictions. However, the emergence of resistant clones is an inevitable limitation of therapies targeting these addictions. Alternative approaches to cancer treatment are therefore required. We propose here a novel approach, based on the notion of conflicting signals and on a phenotypic description of cancer cells. "Phenotype" is an inherently complex notion that we describe in the conceptual framework of the epigenetic landscape, with a view to bridging the gap between theory and practice at the patient's bedside...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27869167/cystine-addiction-of-triple-negative-breast-cancer-associated-with-emt-augmented-death-signaling
#15
X Tang, C-K Ding, J Wu, J Sjol, S Wardell, I Spasojevic, D George, D P McDonnell, D S Hsu, J T Chang, J-T Chi
Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27845970/role-of-the-unfolded-protein-response-in-tumor-cell-characteristics-and-cancer-outcome
#16
Antoine Galmiche, Chloé Sauzay, Eric Chevet, Olivier Pluquet
PURPOSE OF REVIEW: In the present review, we discuss the possible role of the unfolded protein response (UPR) in the acquisition of tumor cell characteristics and in the prognosis of cancer outcome, which could assist and contribute to the development of more promising therapeutic strategies. RECENT FINDINGS: Accumulating evidence supports the idea that alteration of endoplasmic reticulum proteostasis is a key player in cancer development and aggressiveness. Some UPR components were reported as independent prognostic biomarker...
January 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/27845331/brca1-regulated-rrm2-expression-protects-glioblastoma-cells-from-endogenous-replication-stress-and-promotes-tumorigenicity
#17
Rikke D Rasmussen, Madhavsai K Gajjar, Lucie Tuckova, Kamilla E Jensen, Apolinar Maya-Mendoza, Camilla B Holst, Kjeld Møllgaard, Jane S Rasmussen, Jannick Brennum, Jiri Bartek, Martin Syrucek, Eva Sedlakova, Klaus K Andersen, Marie H Frederiksen, Jiri Bartek, Petra Hamerlik
Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis...
November 15, 2016: Nature Communications
https://www.readbyqxmd.com/read/27843631/unravelling-signal-escape-through-maintained-egfr-activation-in-advanced-non-small-cell-lung-cancer-nsclc-new-treatment-options
#18
REVIEW
Jordi Remon, Benjamin Besse
The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation...
2016: ESMO Open
https://www.readbyqxmd.com/read/27835915/unveiling-changes-in-the-landscape-of-patient-populations-in-cancer-early-drug-development
#19
REVIEW
Cinta Hierro, Analía Azaro, Guillem Argilés, Elena Elez, Patricia Gómez, Joan Carles, Jordi Rodon
The introduction of new Molecularly Targeted Agents (MTA) has changed the landscape in Early Drug Development (EDD) over the last two decades, leading to an improvement in clinical trial design. Previous Phase 1 (Ph1) studies with cytotoxics focused on safety objectives, only recruiting heavily pre-treated cancer patients, have been left behind. In this review, we will illustrate the slow although unstoppable change that has increasingly been observed in those populations candidate to participate in EDD trials with the advent of MTA...
November 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27822137/axitinib-has-antiangiogenic-and-antitumorigenic-activity-in-myxoid-liposarcoma
#20
Lauren T Kerr, Jacqueline F Donoghue, Alexander L Wilding, Terrance G Johns
Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The small molecule inhibitor axitinib, which targets angiogenesis by inhibiting the VEGFR and PDGFR families and c-Kit, inhibited cell cycle progression and induced apoptosis in vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice...
2016: Sarcoma
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