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https://www.readbyqxmd.com/read/29348439/dual-suppression-of-inner-and-outer-mitochondrial-membrane-functions-augments-apoptotic-responses-to-oncogenic-mapk-inhibition
#1
Madhavika N Serasinghe, Jesse D Gelles, Kent Li, Lauren Zhao, Franco Abbate, Marie Syku, Jarvier N Mohammed, Brateil Badal, Cuahutlehuanitzin A Rangel, Kyle L Hoehn, Julide Tok Celebi, Jerry Edward Chipuk
Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAFV600E melanoma cells eliminate glycolysis upon inhibition of BRAFV600E or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. As the inner mitochondrial membrane (IMM) is sub-organellar site of oxidative phosphorylation (OXPHOS), and the outer mitochondrial membrane (OMM) is the major site of anti-apoptotic BCL-2 protein function, we hypothesized that suppressing these critical mitochondrial membrane functions would be a rational approach to maximize the pro-apoptotic effect of MAPK inhibition...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29346301/braf-and-mek-inhibitors-influence-the-function-of-reprogrammed-t-cells-consequences-for-adoptive-t-cell-therapy
#2
Jan Dörrie, Lek Babalija, Stefanie Hoyer, Kerstin F Gerer, Gerold Schuler, Lucie Heinzerling, Niels Schaft
BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs...
January 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29343524/antitumor-properties-of-raf709-a-highly-selective-and-potent-inhibitor-of-raf-kinase-dimers-in-tumors-driven-by-mutant-ras-or-braf
#3
Wenlin Shao, Yuji Mishina, Yun Feng, Giordano Caponigro, Vesselina G Cooke, Stacy Rivera, Yingyun Wang, Fang Shen, Joshua M Korn, Lesley Mathews Griner, Gisele Nishiguchi, Alice Rico, John Tellew, Jacob Haling, Robert Aversa, Valery R Polyakov, Richard Zang, Mohammad Hekmat-Nejad, Payman Amiri, Mallika Singh, Nicholas Keen, Michael P Dillon, Emma Lees, Savithri Ramurthy, William R Sellers, Darrin D Stuart
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29343212/clinical-characteristics-of-subtypes-of-follicular-variant-papillary-thyroid-carcinoma
#4
Min Joo Kim, Jae-Kyung Won, Kyeong Cheon Jung, Ji-Hoon Kim, Sun Wook Cho, Do Joon Park, Young Joo Park
Background Among follicular variant papillary thyroid carcinomas (FVPTCs), the non-invasive encapsulated subtype has an excellent prognosis. For this reason, re-classification of non-invasive encapsulated FVPTC (EFVPTC) as a new entity called "non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" has been proposed, but controversy remains. To characterize non-invasive EFVPTC in an Asian population, we compared the clinicopathological features of each FVPTC subtype in a Korean population...
January 17, 2018: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/29342254/distinctive-desmoplastic-3d-morphology-associated-with-brafv600e-in-papillary-thyroid-cancers
#5
M Tarabichi, A Antoniou, S Le Pennec, D Gacquer, N de Saint Aubain, L Craciun, T Cielen, I Laios, D Larsimont, G Andry, J E Dumont, C Maenhaut, V Detours
Context: Although 60% of papillary thyroid carcinomas are BRAFV600E mutant (PTCV600E), the higher aggressiveness of these cancers is still debated. Objective: In PTCV600E we aimed to further characterize the extent of the stroma and its activation, the 3D tumor-stroma interface, and the proliferation rates of tumor and stromal fibroblasts. Design: We analyzed exomes, trancriptomes and images of 364 PTC from The Cancer Genome Atlas (TCGA), including 211 PTCV600E; stained 22 independent PTC for BRAFV600E and Ki67; sequenced the exomes and stained BRAFV600E in 5 primary tumor blocks and 4 nodal metastases from one PTCV600E patient; and reconstructed the 3D volumes of one tumor and one metastatic blocks at histological resolution...
January 12, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29332123/braf-nras-and-gnaq-mutations-in-conjunctival-melanocytic-nevi
#6
Jasmine H Francis, Hans E Grossniklaus, Larissa A Habib, Brian Marr, David H Abramson, Klaus J Busam
Purpose: To evaluate BRAF, NRAS, and GNAQ mutations in surgical specimens of common and blue conjunctival melanocytic nevi. Methods: Surgical specimens from 25 conjunctival melanocytic nevi (23 common and 2 blue) of 25 patients were evaluated. All common nevi were analyzed immunohistochemically for the expression of BRAF V600E or NRAS Q61R. One lesion with negative immunoreactivity and for all blue nevi, a hybridization capture-based next-generation sequencing method was employed for mutation analysis...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29326440/braf-inhibition-upregulates-a-variety-of-receptor-tyrosine-kinases-and-their-downstream-effector-gab2-in-colorectal-cancer-cell-lines
#7
Ricarda Herr, Sebastian Halbach, Miriam Heizmann, Hauke Busch, Melanie Boerries, Tilman Brummer
BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29316976/clinical-implications-of-the-braf-mutation-in-papillary-thyroid-carcinoma%C3%A2-and-chronic-lymphocytic-thyroiditis
#8
Woon Won Kim, Tae Kwun Ha, Sung Kwon Bae
BACKGROUND: The purpose of this study was to examine the possible prognostics and clinicopathologic characteristics underlying the BRAFV600E mutation and papillary thyroid carcinoma (PTC) coexisting or in absence of chronic lymphocytic thyroiditis (CLT). METHODS: This study was conducted on 172 patients who had undergone total thyroidectomy or unilateral total thyroidectomy for PTC; the patients were then examined for the BRAFV600E mutation using specimens obtained after their surgery from January 2013 to August 2015...
January 9, 2018: Journal of Otolaryngology—Head & Neck Surgery
https://www.readbyqxmd.com/read/29312770/development-of-pulmonary-langerhans-cell-histiocytosis-in-a-patient-with-established-adenocarcinoma-of-the-lung
#9
Or Kalchiem-Dekel, Adina Paulk, Seth J Kligerman, Allen P Burke, Nirav G Shah, Renee K Dixon
Newly-appearing lung nodules on surveillance imaging in patients with pre-existing lung cancer can present a diagnostic dilemma when attempting to differentiate between metastatic disease, infection, and other inflammatory conditions. Here we report a case of an EGFR-/ALK-/BRAF+ metastatic adenocarcinoma patient who underwent lung biopsy for evaluation of upper-lobe predominant lung nodules revealed to represent pulmonary Langerhans cell histiocytosis (PLCH). The patient was a heavy smoker and admitted to increase her smoking habit after initially learning about her diagnosis with lung cancer...
December 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/29304767/mlh1-93%C3%A2-g-a-polymorphism-is-associated-with-mlh1-promoter-methylation-and-protein-loss-in-dysplastic-sessile-serrated-adenomas-with-brafv600e-mutation
#10
Lochlan J Fennell, Saara Jamieson, Diane McKeone, Tracie Corish, Megan Rohdmann, Tori Furner, Mark Bettington, Cheng Liu, Futoshi Kawamata, Catherine Bond, Jolieke Van De Pols, Barbara Leggett, Vicki Whitehall
BACKGROUND: Sessile serrated adenomas with BRAF mutation progress rapidly to cancer following the development of dysplasia (SSAD). Approximately 75% of SSADs methylate the mismatch repair gene MLH1, develop mismatch repair deficiency and the resultant cancers have a good prognosis. The remaining SSADs and BRAF mutant traditional serrated adenomas (TSA) develop into microsatellite stable cancers with a poor prognosis. The reason for this dichotomy is unknown. In this study, we assessed the genotypic frequency of the MLH1-93 polymorphism rs1800734 in SSADs and TSAs to determine if the uncommon variant A allele predisposes to MLH1 promoter hypermethylation...
January 5, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29298843/nis-expression-in-thyroid-tumors-relation-with-prognosis-clinicopathological-and-molecular-features
#11
Catarina Tavares, Maria João Coelho, Catarina Eloy, Miguel Melo, Adriana Gaspar da Rocha, Ana Pestana, Rui Batista, Luciana Bueno Ferreira, Elisabete Rios, Samia Selmi-Ruby, Bruno Cavadas, Luísa Pereira, Manuel Sobrinho Simões, Paula Soares
Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the SLC5A5 gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied SLC5A5 expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database...
January 2018: Endocrine Connections
https://www.readbyqxmd.com/read/29296862/brafv600e-accelerates-disease-progression-and-enhances-immune-suppression-in-a-mouse-model-of-b-cell-leukemia
#12
Yo-Ting Tsai, Aparna Lakshmanan, Amy Lehman, Bonnie K Harrington, Fabienne McClanahan Lucas, Minh Tran, Ellen J Sass, Meixiao Long, Alan D Flechtner, Florinda Jaynes, Krista La Perle, Vincenzo Coppola, Gerard Lozanski, Natarajan Muthusamy, John C Byrd, Michael R Grever, David M Lucas
Mutated mitogen-activated protein kinase (MAPK) pathway components promote tumor survival, proliferation, and immune evasion in solid tumors. MAPK mutations occur in hematologic cancers as well, but their role is less clear and few models are available to study this. We developed an in vivo model of disseminated BRAFV600E B-cell leukemia to determine the effects of this mutation on tumor development and immune evasion. Mice with B-cell-restricted BRAFV600E expression crossed with the Eµ-TCL1 model of chronic lymphocytic leukemia (CLL) developed leukemia significantly earlier (median, 4...
November 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/29288729/extracellular-vesicles-or-free-circulating-dna-where-to-search-for-braf-and-ckit-mutations
#13
Jennifer Klump, Ulrike Philipp, Marie Follo, Anna Eremin, Hannes Lehmann, Sigrun Nestel, Nikolas von Bubnoff, Irina Nazarenko
Clinical evidence in oncology argues for the advantages of performing molecular analysis of blood biomarkers to provide information about systemic changes and tumor heterogeneity. Whereas the diagnostic value of cell-free circulating DNA (fcDNA) has successfully been demonstrated in several studies, DNA enclosed in extracellular vesicles (EV) has only recently been described, and its potential diagnostic value is unclear. We established a protocol for separation of EV and fc fractions and tested for presence of mutant BRAFV600E mediating resistance to Vemurafenib and cKITD816V mediating resistance to Imatinib in blood of patients with melanoma and mastocytosis...
December 27, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29285228/four-month-course-of-adjuvant-dabrafenib-in-patients-with-surgically-resected-stage-iiic-melanoma-characterized-by-a-brafv600e-k-mutation
#14
Parisa Momtaz, James J Harding, Charlotte Ariyan, Daniel G Coit, Taha Merghoub, Billel Gasmi, Daoqi You, Agnes Viale, Katherine S Panageas, Aliaksandra Samoila, Michael A Postow, Jedd D Wolchok, Paul B Chapman
Background: We tested the hypothesis that a 4-month course of adjuvant dabrafenib in stage IIIC BRAF-mutated melanoma would improve 2 year RFS from 24% to 51%, and that tumor-derived cell free DNA (cfDNA) in plasma would correlate with and predict recurrence. Methods: Patients with stage IIIC BRAF V600E/K mutated melanoma who were free of disease after surgical resection received 4 months of adjuvant dabrafenib. Patients were evaluated with imaging at baseline, at the end of cycles 2, 4, 6, then every 3 months until disease relapse or 2 years, whichever came first...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29281831/degree-of-tissue-differentiation-dictates-susceptibility-to-braf-driven-colorectal-cancer
#15
Kevin Tong, Oscar Pellón-Cárdenas, Veerin R Sirihorachai, Bailey N Warder, Om A Kothari, Ansu O Perekatt, Emily E Fokas, Robert L Fullem, Anbo Zhou, Joshua K Thackray, Hiep Tran, Lanjing Zhang, Jinchuan Xing, Michael P Verzi
Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of BRAFV600E is amplified...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29249695/gdc-0879-a-brafv600e-inhibitor-protects-kidney-podocytes-from-death
#16
Jonas Sieber, Nicolas Wieder, Abbe Clark, Manuel Reitberger, Sofia Matan, Jeannine Schoenfelder, Jianming Zhang, Anna Mandinova, Joshua Adam Bittker, Juan Gutierrez, Ozan Aygün, Namrata Udeshi, Steven Carr, Peter Mundel, Andreas Werner Jehle, Anna Greka
Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds...
December 6, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29241739/braf-and-kras-mutations-in-tubular-apocrine-adenoma-and-papillary-eccrine-adenoma-of-the-skin
#17
Jau-Yu Liau, Jia-Huei Tsai, Wen-Chang Huang, Jui Lan, Jin-Bon Hong, Chang-Tsu Yuan
Tubular apocrine adenoma (TAA) and papillary eccrine adenoma (PEA) are benign sweat gland tumors. Their names imply that they exhibit apocrine and eccrine differentiation, respectively. However, morphologically they are very similar and are often indistinguishable. The molecular pathogenesis of either tumor is poorly understood at present. On the basis of an index case of nipple adenoma that was morphologically reminiscent of cutaneous TAA/PEA and harbored a BRAFV600E mutation, we investigated whether a similar genetic change is also present in TAA/PEA...
December 11, 2017: Human Pathology
https://www.readbyqxmd.com/read/29235576/the-unfolded-protein-response-impacts-melanoma-progression-by-enhancing-fgf-expression-and-can-be-antagonized-by-a-chemical-chaperone
#18
Karin Eigner, Yüksel Filik, Florian Mark, Birgit Schütz, Günter Klambauer, Richard Moriggl, Markus Hengstschläger, Herbert Stangl, Mario Mikula, Clemens Röhrl
The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells...
December 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29233910/targeting-cdk1-and-mek-erk-overcomes-apoptotic-resistance-in-braf-mutated-human-colorectal-cancer
#19
Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Strebhardt, Kaixiong Tao, Shengbing Huang, Frank A Sinicrope
The BRAFV600E mutation occurs in ~8% of human colorectal cancers (CRCs) and is associated with therapeutic resistance that is due, in part, to re-activation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E CRCs. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells. BRAFV600E CRC cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1,2,5,9 inhibitor)...
December 12, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29229836/single-cell-analysis-resolves-the-cell-state-transition-and-signaling-dynamics-associated-with-melanoma-drug-induced-resistance
#20
Yapeng Su, Wei Wei, Lidia Robert, Min Xue, Jennifer Tsoi, Angel Garcia-Diaz, Blanca Homet Moreno, Jungwoo Kim, Rachel H Ng, Jihoon W Lee, Richard C Koya, Begonya Comin-Anduix, Thomas G Graeber, Antoni Ribas, James R Heath
Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-derived BRAFV600 -mutant melanoma cell lines. A subset of plastic cell lines, which followed a trajectory covering multiple known cell state transitions, provided models for more detailed biophysical investigations...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
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