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https://www.readbyqxmd.com/read/27890930/histone-deacetylase-inhibitors-interrupt-hsp90-rasgrp1-and-hsp90-craf-interactions-to-upregulate-bim-and-circumvent-drug-resistance-in-lymphoma-cells
#1
H Ding, K L Peterson, C Correia, B Koh, P A Schneider, G S Nowakowski, S H Kaufmann
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here we show that trichostatin A, romidepsin, and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine, and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27846237/integrated-genomics-identifies-mir-32-mcl-1-pathway-as-a-critical-driver-of-melanomagenesis-implications-for-mir-replacement-and-combination-therapy
#2
Prasun J Mishra, Pravin J Mishra, Glenn Merlino
AIMS: Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous...
2016: PloS One
https://www.readbyqxmd.com/read/27820802/inhibition-of-ras-function-through-targeting-an-allosteric-regulatory-site
#3
Russell Spencer-Smith, Akiko Koide, Yong Zhou, Raphael R Eguchi, Fern Sha, Priyanka Gajwani, Dianicha Santana, Ankit Gupta, Miranda Jacobs, Erika Herrero-Garcia, Jacqueline Cobbert, Hugo Lavoie, Matthew Smith, Thanashan Rajakulendran, Evan Dowdell, Mustafa Nazir Okur, Irina Dementieva, Frank Sicheri, Marc Therrien, John F Hancock, Mitsuhiko Ikura, Shohei Koide, John P O'Bryan
RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1...
November 7, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27753529/cyclin-g2-promotes-cell-cycle-arrest-in-breast-cancer-cells-responding-to-fulvestrant-and-metformin-and-correlates-with-patient-survival
#4
Maike Zimmermann, Aruni P S Arachchige-Don, Michaela S Donaldson, Tommaso Patriarchi, Mary C Horne
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest...
October 18, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27703006/bipartite-role-of-heat-shock-protein-90-hsp90-keeps-craf-kinase-poised-for-activation
#5
Shahana Mitra, Baijayanti Ghosh, Nilanjan Gayen, Joydeep Roy, Atin K Mandal
CRAF kinase maintains cell viability, growth, and proliferation by participating in the MAPK pathway. Unlike BRAF, CRAF requires continuous chaperoning by Hsp90 to retain MAPK signaling. However, the reason behind the continuous association of Hsp90 with CRAF is still elusive. In this study, we have identified the bipartite role of Hsp90 in chaperoning CRAF kinase. Hsp90 facilitates Ser-621 phosphorylation of CRAF and prevents the kinase from degradation. Co-chaperone Cdc37 assists in this phosphorylation event...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27678303/erianin-inhibits-high-glucose-induced-retinal-angiogenesis-via-blocking-erk1-2-regulated-hif-1%C3%AE-vegf-vegfr2-signaling-pathway
#6
Zengyang Yu, Tianyu Zhang, Chenyuan Gong, Yuchen Sheng, Bin Lu, Lingyu Zhou, Lili Ji, Zhengtao Wang
Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells...
September 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27577079/non-v600-braf-mutations-recurrently-found-in-lung-cancer-predict-sensitivity-to-the-combination-of-trametinib-and-dabrafenib
#7
Amir Noeparast, Erik Teugels, Philippe Giron, Gil Verschelden, Sylvia De Brakeleer, Lore Decoster, Jacques De Grève
Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ~40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner...
August 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27571413/chemically-linked-vemurafenib-inhibitors-promote-an-inactive-braf-v600e-conformation
#8
Michael Grasso, Michelle A Estrada, Christian Ventocilla, Minu Samanta, Jasna Maksimoska, Jessie Villanueva, Jeffrey D Winkler, Ronen Marmorstein
The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAF(V600E)) accounts for about 90% of these activating mutations. While BRAF(V600E)-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance. Resistance often arises through reactivation of the MAPK pathway, typically through mutation of upstream RAS, downstream MEK, or splicing variants...
October 21, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27448964/mir-7-reverses-the-resistance-to-brafi-in-melanoma-by-targeting-egfr-igf-1r-craf-and-inhibiting-the-mapk-and-pi3k-akt-signaling-pathways
#9
Xiaoyan Sun, Jun Li, Yanhong Sun, Yi Zhang, Liyun Dong, Chen Shen, Liu Yang, Ming Yang, Yan Li, Guanxin Shen, Yating Tu, Juan Tao
MicroRNAs (miRNAs) are attractive therapeutic targets for various therapy-resistant tumors. However, the association between miRNA and BRAF inhibitor resistance in melanoma remains to be elucidated. We used microarray analysis to comprehensively study the miRNA expression profiling of vemurafenib resistant (VemR) A375 melanoma cells in relation to parental A375 melanoma cells. MicroRNA-7 (miR-7) was identified to be the most significantly down-regulated miRNA in VemR A375 melanoma cells. We also found that miR-7 was down-regulated in Mel-CVR cells (vemurafenib resistant Mel-CV melanoma cells)...
July 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27321184/inhibition-of-the-craf-prohibitin-interaction-reverses-craf-dependent-resistance-to-vemurafenib
#10
N A Doudican, S J Orlow
Activating BRAF mutations promote constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and are common in a variety of human malignancies, including melanoma and colon cancer. Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy. However, resistance typically emerges in most melanoma patients. Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma...
June 20, 2016: Oncogene
https://www.readbyqxmd.com/read/27279914/adaptive-and-acquired-resistance-to-egfr-inhibitors-converge-on-the-mapk-pathway
#11
Pengfei Ma, Yujie Fu, Minjiang Chen, Ying Jing, Jie Wu, Ke Li, Ying Shen, Jian-Xin Gao, Mengzhao Wang, Xiaojing Zhao, Guanglei Zhuang
Both adaptive and acquired resistance significantly limits the efficacy of the epidermal growth factor receptor (EGFR) kinase inhibitors. However, the distinct or common mechanisms of adaptive and acquired resistance have not been fully characterized. Here, through systematic modeling of erlotinib resistance in lung cancer, we found that feedback reactivation of MAPK signaling following erlotinib treatment, which was dependent on the MET receptor, contributed to the adaptive resistance of EGFR inhibitors. Interestingly, acquired resistance to erlotinib was also associated with the MAPK pathway activation as a result of CRAF or NRAS amplification...
2016: Theranostics
https://www.readbyqxmd.com/read/27273450/craf-r391w-is-a-melanoma-driver-oncogene
#12
Mohammad Atefi, Bjoern Titz, Jennifer Tsoi, Earl Avramis, Allison Le, Charles Ng, Anastasia Lomova, Amanda Lassen, Michael Friedman, Bartosz Chmielowski, Antoni Ribas, Thomas G Graeber
Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27196768/egfr-mediated-reactivation-of-mapk-signaling-induces-acquired-resistance-to-gsk2118436-in-braf-v600e-mutant-nsclc-cell-lines
#13
Sung-Moo Kim, Hwan Kim, Kang Won Jang, Min Hwan Kim, Jinyoung Sohn, Mi Ran Yun, Han Na Kang, Chan Woo Kang, Hye Ryun Kim, Sun Min Lim, Yong Wha Moon, Joo Hang Kim, Soonmyung Paik, Byoung Chul Cho
Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436...
July 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27061517/pediatric-gliomas-with-craf-fusions-may-require-combination-treatment
#14
Carrie Printz
No abstract text is available yet for this article.
April 15, 2016: Cancer
https://www.readbyqxmd.com/read/27025703/optogenetically-controlled-raf-to-characterize-braf-and-craf-protein-kinase-inhibitors
#15
Claire V Chatelle, Désirée Hövermann, Anne Müller, Hanna J Wagner, Wilfried Weber, Gerald Radziwill
Here, we applied optoRAF, an optogenetic tool for light-controlled clustering and activation of RAF proteins that mimics the natural occurring RAS-mediated dimerization. This versatile tool allows studying the effect on BRAF and CRAF homodimer- as well as heterodimer-induced RAF signaling. Vemurafenib and dabrafenib are two clinically approved inhibitors for BRAF that efficiently suppress the kinase activity of oncogenic BRAF (V600E). However in wild-type BRAF expressing cells, BRAF inhibitors can exert paradoxical activation of wild-type CRAF...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27003818/polo-like-kinase-1-induces-epithelial-to-mesenchymal-transition-and-promotes-epithelial-cell-motility-by-activating-craf-erk-signaling
#16
Jianguo Wu, Andrei I Ivanov, Paul B Fisher, Zheng Fu
Polo-like kinase 1 (PLK1) is a key cell cycle regulator implicated in the development of various cancers, including prostate cancer. However, the functions of PLK1 beyond cell cycle regulation remain poorly characterized. Here, we report that PLK1 overexpression in prostate epithelial cells triggers oncogenic transformation. It also results in dramatic transcriptional reprogramming of the cells, leading to epithelial-to-mesenchymal transition (EMT) and stimulation of cell migration and invasion. Consistently, PLK1 downregulation in metastatic prostate cancer cells enhances epithelial characteristics and inhibits cell motility...
2016: ELife
https://www.readbyqxmd.com/read/26959608/tumor-cells-with-kras-or-braf-mutations-or-erk5-mapk7-amplification-are-not-addicted-to-erk5-activity-for-cell-proliferation
#17
Pamela A Lochhead, Jonathan Clark, Lan-Zhen Wang, Lesley Gilmour, Matthew Squires, Rebecca Gilley, Caroline Foxton, David R Newell, Stephen R Wedge, Simon J Cook
ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as a cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated by MEK5. It has been proposed that RAS and RAF proteins can also promote ERK5 activation. Here we investigated the interplay between RAS-RAF-MEK-ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models. We demonstrate that although an inducible form of CRAF (CRAF:ER*) can activate ERK5 in fibroblasts, the response is delayed and reflects feed-forward signaling...
2016: Cell Cycle
https://www.readbyqxmd.com/read/26885666/registered-report-kinase-dead-braf-and-oncogenic-ras-cooperate-to-drive-tumor-progression-through-craf
#18
Ajay Bhargava, Madan Anant, Hildegard Mack
The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF" by Heidorn and colleagues, published in Cell in 2010 (Heidorn et al...
2016: ELife
https://www.readbyqxmd.com/read/26882073/registered-report-raf-inhibitors-prime-wild-type-raf-to-activate-the-mapk-pathway-and-enhance-growth
#19
Ajay Bhargava, Steven Pelech, Ben Woodard, John Kerwin, Nimet Maherali
The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from 'RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth' by Hatzivassiliou and colleagues, published in Nature in 2010 (Hatzivassiliou et al...
2016: ELife
https://www.readbyqxmd.com/read/26870784/a-novel-class-of-small-molecule-compounds-that-inhibit-hepatitis-c-virus-infection-by-targeting-the-prohibitin-craf-pathway
#20
Shufeng Liu, Wenyu Wang, Lauren E Brown, Chao Qiu, Neil Lajkiewicz, Ting Zhao, Jianhua Zhou, John A Porco, Tony T Wang
Identification of novel drug targets and affordable therapeutic agents remains a high priority in the fight against chronic hepatitis C virus (HCV) infection. Here, we report that the cellular proteins prohibitin 1 (PHB1) and 2 (PHB2) are pan-genotypic HCV entry factors functioning at a post-binding step. While predominantly found in mitochondria, PHBs localize to the plasma membrane of hepatocytes through their transmembrane domains and interact with both EGFR and CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 and 2, reduced cell surface PHB1 and 2, disrupted PHB-CRaf interaction, and inhibited HCV entry at low nanomolar concentrations...
November 2015: EBioMedicine
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