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Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
N V Apanovich, M V Peters, P V Apanovich, B Sh Kamolov, V B Matveev, E K Ginter, A V Karpukhin
The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3...
January 2018: Doklady. Biochemistry and Biophysics
Marcel Wiesweg, Henning Reis, Tobias Köster, Moritz Goetz, Karl Worm, Thomas Herold, Andreas Paul, Alexander Dechêne, Brigitte Schumacher, Peter Markus, Isabel Virchow, Karina Kostbade, Nathalie Wolf, Gregor Zaun, Martin Metzenmacher, Kurt W Schmid, Martin Schuler, Stefan Kasper
BACKGROUND: Deregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes. PATIENTS AND METHODS: A prospectively studied cohort of 160 patients with metastatic CRC was included. Standard diagnostic workup included mutational analyses of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF)...
February 17, 2018: Clinical Colorectal Cancer
Witold Owczarek, Monika Słowińska, Aleksandra Lesiak, Magdalena Ciążyńska, Aldona Maciąg, Elwira Paluchowska, Luiza Marek-Józefowicz, Rafał Czajkowski
Overexpression of the epidermal growth factor receptor (EGFR) is found in many cancers, including those of the head and neck area, non-small-cell lung cancer, and colorectal, cervical, prostate, breast, ovary, stomach, and pancreatic cancer. The EGFR inhibitors are used at present in the treatment of such cancers. Skin lesions that develop during and after cancer treatment may be due to specific cytostatics, molecular-targeted drugs, radiation therapy, complementary therapy, or the cancer itself, and hence knowledge is essential to distinguish between them...
October 2017: Postȩpy Dermatologii i Alergologii
Akihiko Sugimoto, Tatsuki R Kataoka, Chiyuki Ueshima, Yusuke Takei, Kyohei Kitamura, Masahiro Hirata, Takashi Nomura, Hironori Haga
The signaling lymphocytic activation molecule family member 8 (SLAMF8)/CD353 is a member of the CD2 family of proteins. Its ligand has not been identified. SLAMF8 is expressed by macrophages and suppresses cellular functions. No study has yet explored SLAMF8 expression or function in human mastocytosis, which features oncogenic KIT-mediated proliferation of human mast cells. SLAMF8 protein was expressed in human mastocytosis cells, immunohistochemically. SLAMF8 expression was also evident in the human mast cell lines, HMC1...
March 2, 2018: Experimental Dermatology
Zhicheng Wang, Jun Cui, Jian Song, Haoze Wang, Kailun Gao, Xuemei Qiu, Meng Gou, Xin Li, Ziwen Hu, Xiuli Wang, Yaqing Chang
Heterosis is important for sea cucumber breeding, but its molecular mechanism remains largely unexplored. In this study, parental lines of Apostichopus japonicus from Russia (R) and China (C) were used to construct hybrids (CR and RC) by reciprocal crossing. We examined the transcriptional profiles of the hybrids (CR and RC) and the purebreds (CC and RR) at different developmental times. A total of 60.27 Gb of clean data was obtained, and 176,649 unigenes were identified, of which 50,312 unigenes were annotated...
February 28, 2018: Marine Biotechnology
Hao Tian, Li Yin, Kai Ding, You-You Xia, Xiao-Hong Wang, Jian-Zhong Wu, Xia He
Raf-1 proto-oncogene, serine/threonine kinase (Raf1) acts as a part of the RAS/RAF/MEK/ERK signaling pathway and regulates cell migration, apoptosis and differentiation. However, few studies are available on the expression and clinical significance of Raf1 in non‑small cell lung cancer (NSCLC). This study investigated the clinical value and prognostic significance of Raf1 in NSCLC patients, following radiotherapy. We evaluated the Raf1 expression using immunohistochemical analyses of samples from 110 NSCLC patients who received radiotherapy...
February 22, 2018: Oncology Reports
Yijun Gao, Matthew T Chang, Daniel McKay, Na Na, Bing Zhou, Rona D Yaeger, Neilawattie M Torres, Keven Muniz, Matthias Drosten, Mariano Barbacid, Giordano Caponigro, Darrin Stuart, Henrik Moebitz, David B Solit, Omar I Abdel-Wahab, Barry S Taylor, Zhan Yao, Neal Rosen
Mutations at multiple sites in MEK1 occur in cancer suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS-RAF dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output and often co-occur with RAS or RAF mutations. They act as amplifiers of RAF signaling. By contrast, another class of mutants delete a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity...
February 26, 2018: Cancer Discovery
Xiaoyu Guo, Wenjing Zhao, Zuojia Liu, Jin Wang
Ras-targeted therapy represents a 'holy grail' in oncology. Based on our model prediction, Spiclomazine freezing the intermediate conformation of activated Ras is central to cancer therapeutics. We show here that Spiclomazine leads to an effective suppression in Ras-mediated signaling through abrogating the KRas-GTP level in the KRas -driven pancreatic cancer. The Ras-mediated signaling inhibition leads to dramatically reduced survivals of five KRas -driven pancreatic cancer cell lines with IC50 ranging 19...
January 23, 2018: Oncotarget
Andrew M Kidger, James Sipthorp, Simon J Cook
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons...
February 15, 2018: Pharmacology & Therapeutics
Zhou Wang, Lingman Ma, Mengqi Su, Yiran Zhou, Ke Mao, Chengqin Li, Guangyong Peng, Changlin Zhou, Baiyong Shen, Jie Dou
Baicalin is a natural flavonoid glycoside which has potent anti-tumor and antioxidant activity in cancer cells. In the present study, we found that baicalin treatment significantly induced senescence in colon cancer cells. Furthermore, baicalin upregulated the expression of decidual protein induced by progesterone (DEPP) in HCT116 colon cancer cells, which accompanied with the activation of Ras/Raf/MEK/ERK and p16 INK4A /Rb signaling pathways. Meanwhile, these phenomena also appeared under the anti-oxidation effect exerted by baicalin...
February 13, 2018: Cell Death & Disease
Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A Schwarz, Roderich E Schwarz
Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC...
January 12, 2018: Oncotarget
Raj Bhayadia, Kathrin Krowiorz, Nadine Haetscher, Razan Jammal, Stephan Emmrich, Askar Obulkasim, Jan Fiedler, Adrian Schwarzer, Arefeh Rouhi, Michael Heuser, Susanne Wingert, Sabrina Bothur, Konstanze Döhner, Tobias Mätzig, Michelle Ng, Dirk Reinhardt, Hartmut Döhner, C Michel Zwaan, Marry van den Heuvel Eibrink, Dirk Heckl, Maarten Fornerod, Thomas Thum, R Keith Humphries, Michael A Rieger, Florian Kuchenbauer, Jan-Henning Klusmann
Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo...
February 12, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
M Prieto-Barrios, R Llamas-Martin, V Velasco-Tamariz, A Calleja-Algarra, Y Ruano, P L Ortiz-Romero, J L Rodriguez-Peralto
A 17-year-old male presented with a large sebaceous naevus (SN) comprising part of his left face and scalp and a speckled lentiginous naevus (SLN) on his right trunk, hip, neck and scalp with a checkerboard pattern. His right oral hemimucosa showed extensive papillomatous lesions which were contiguous to the upper lip SN lesions. As for extracutaneous manifestations he suffered from cardiac, musculoskeletal and ocular alterations. On the other hand, he developed two primary rhabdomyosarcomas. DNA samples of the SN, SLN, the oral papillomatous hyperplasia and both rhabdomyosarcomas were analyzed by Sanger sequencing...
February 12, 2018: British Journal of Dermatology
Peter Dietrich, Kim Freese, Abdo Mahli, Wolfgang Erwin Thasler, Claus Hellerbrand, Anja Katrin Bosserhoff
Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo-like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling...
January 9, 2018: Oncotarget
Shrivani Sriskanthadevan-Pirahas, Rujuta Deshpande, Byoungchun Lee, Savraj S Grewal
The small G-protein Ras is a conserved regulator of cell and tissue growth. These effects of Ras are mediated largely through activation of a canonical RAF-MEK-ERK kinase cascade. An important challenge is to identify how this Ras/ERK pathway alters cellular metabolism to drive growth. Here we report on stimulation of RNA polymerase III (Pol III)-mediated tRNA synthesis as a growth effector of Ras/ERK signalling in Drosophila. We find that activation of Ras/ERK signalling promotes tRNA synthesis both in vivo and in cultured Drosophila S2 cells...
February 5, 2018: PLoS Genetics
Venkat Bhat, Sujitha Srinathan, Elisa Pasini, Marc Angeli, Emily Chen, Cristina Baciu, Mamatha Bhat
AIM: To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis. METHODS: PubMed and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks...
January 27, 2018: World Journal of Hepatology
Quqing Song, Sheng Jiang, Xinxin Zhang, Chunxia Pan, Chunhua Lu, Jingwei Peng, Qingshui Li
Ovarian cancer has the highest mortality rate among gynecological cancers; the most effective therapy for this cancer is a combination of radiation treatment and chemotherapy. However, radiation resistance is the leading factor associated with treatment failure. The present study aimed to investigate pseudolaric acid B (PAB) as a potential radiosensitizer for the treatment of ovarian cancer. The present study performed MTT and clonogenic assays, and demonstrated that PAB could induce a radiosensitizing effect on SKOV-3 cells...
January 2018: Experimental and Therapeutic Medicine
Manuel Sanclemente, Sarah Francoz, Laura Esteban-Burgos, Emilie Bousquet-Mur, Magdolna Djurec, Pedro P Lopez-Casas, Manuel Hidalgo, Carmen Guerra, Matthias Drosten, Monica Musteanu, Mariano Barbacid
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V /Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis...
February 12, 2018: Cancer Cell
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