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Melanoma braf resistance

Kohya Kudo, Atsuko Yoneda, Daiki Sakiyama, Kai Kojima, Takeki Miyaji, Miku Yamazaki, Saori Yaita, Takuya Hyodo, Reiko Satow, Kiyoko Fukami
The BRAF inhibitor PLX4032 is effective in treating BRAF-mutated melanoma; however, because drug resistance develops in most cases, it is critical to develop a new strategy for inhibiting drug-resistant melanoma growth. The melanoma-associated membrane glycoprotein CD63 is involved in cell proliferation and metastasis. Here, we found that cell surface CD63 suppresses the proliferation of human melanoma cells and PLX4032-resistant cells. Endogenous CD63 protein levels were negatively correlated with PLX4032 resistance of human melanoma cell lines...
December 3, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Luigi Fattore, Rita Mancini, Paolo Antonio Ascierto, Gennaro Ciliberto
Introduction The advent of targeted therapies and immunecheckpoints inhibitors has enhanced the treatment of metastatic melanomas. Despite striking improvements of patients' survival, drug resistance continues to limit the efficacy of such treatments. Genetic and non genetic/adaptive mechanisms of resistance could be involved; in the latter mechanism, non coding RNAs (ncRNAs) are emerging as key players. Areas covered This article outlines the current knowledge of ncRNA involvement in BRAF-mutant melanomas and the development of resistance to targeted/immuno-therapies...
December 3, 2018: Expert Opinion on Therapeutic Targets
Arran Hodgkinson, Laurent Le Cam, Dumitru Trucu, Ovidiu Radulescu
Although novel targeted therapies have significantly improved the overall survival of patients with advanced melanoma, understanding and combatting drug resistance remains a major clinical challenge. Using partial differential equations, we describe the evolution of a cellular population through time, space, and phenotype dimensions, in the presence of various drug species. We then use this framework to explore models in which resistance is attained by either mutations (irreversible) or plasticity (reversible)...
November 29, 2018: Journal of Theoretical Biology
Delphine Morales, Florian Lombart, Agathe Truchot, Pauline Maire, Marwa Hussein, Warda Hamitou, Pascale Vigneron, Antoine Galmiche, Catherine Lok, Muriel Vayssade
Melanoma cell sensitivity to targeted therapy molecules is dependent on the tumor microenvironment (cell-cell and cell-extracellular matrix interactions). Three dimensional (3D) in vitro cell culture systems better reflect the native structural architecture of tissues and are attractive to investigate cellular interactions. We have developed and compared several metastatic melanoma models: melanoma cells (SK-MEL-28 and SK-MEL-3, BRAF V600E mutant and SK-MEL-2 BRAF wt) cultured as a monolayer (2D) and co-cultured on 3D dermal equivalents with fibroblasts to better unravel factors modulating cell sensitivity to a BRAF inhibitor (BRAFi, vemurafenib)...
December 1, 2018: Tissue Engineering. Part A
David Garandeau, Justine Noujarède, Justine Leclerc, Caroline Imbert, Virginie Garcia, Marie-Lise Bats, Florian Rambow, Julia Gilhodes, Thomas Filleron, Nicolas Meyer, Stéphanie Brayer, Silvia Arcucci, Sophie Tartare-Deckert, Bruno Segui, Jean Christophe Marine, Thierry Levade, Corine Bertolotto, Nathalie Andrieu-Abadie
BRAF inhibitors (BRAFi) are used to treat melanoma patients harboring the V600E mutation. However, resistance to BRAFi is inevitable. Here, we identified sphingosine-1-phosphate (S1P) receptors as regulators of BRAFV600E-mutant melanoma cell-autonomous resistance to BRAFi. Moreover, our results reveal a distinct sphingolipid profile, i.e. a tendency for increased very long-chain ceramide species, in the plasma of melanoma patients who achieve a response to BRAFi therapy as compared to patients with progressive disease...
November 27, 2018: Molecular Cancer Therapeutics
Lenka Sinik, Katherine A Minson, John J Tentler, Jacqueline Carrico, Stacey M Bagby, William A Robinson, Rotem Karni, Tal Burstyn-Cohen, S Gail Eckhardt, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Douglas K Graham
Molecularly-targeted agents have improved outcomes for a subset of patients with BRAF-mutated melanoma, but treatment of resistant and BRAF wild-type tumors remains a challenge. The MERTK receptor tyrosine kinase is aberrantly expressed in melanoma and can contribute to oncogenic phenotypes. Here we report the effect of treatment with a MERTK-selective small molecule inhibitor, UNC2025, in preclinical models of melanoma. In melanoma cell lines, treatment with UNC2025 potently inhibited phosphorylation of MERTK and downstream signaling, induced cell death, and decreased colony formation...
November 27, 2018: Molecular Cancer Therapeutics
Christina Brummer, Stephanie Faerber, Christina Bruss, Christian Blank, Ruben Lacroix, Sebastian Haferkamp, Wolfgang Herr, Marina Kreutz, Kathrin Renner
Tumors, including melanomas, frequently show an accelerated glucose metabolism. Mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) oncogene, detected in about 50 % of all melanomas, result in further enhancement of glycolysis. Therefore anti-metabolic substances might enhance the impact of RAF inhibitors. We have identified the two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib being able to restrict energy metabolism in human melanoma cells by targeting lactate release and oxidative phosphorylation (OXPHOS)...
November 24, 2018: Cancer Letters
Jun Li, Jun Xie, Jintao Zhu, Jun Tao
Malignant melanoma is the most aggressive and lethal form of skin cancer with an increasing incidence worldwide. In the past 5 years, the Food and Drug Administration has approved six targeted therapies or immunotherapies for the treatment of metastatic melanoma (Chapman et al., 2011; Falchook et al., 2012; Hauschild et al., 2012; Hodi et al., 2010; Ribas et al., 2015; Topalian et al., 2014). For the first time, interventions improve survival of this deadly disease. However, rapid resistance to BRAF/MEK inhibitors and lower rates of objective response or immune-related side effects for anti-CTLA-4 or anti-PD-1 monoclonal antibodies limited their widespread clinical applications...
December 2018: Journal of Investigative Dermatology. Symposium Proceedings
Marta Díaz-Martínez, Lucía Benito-Jardón, Joaquin Teixidó
No abstract text is available yet for this article.
October 23, 2018: Oncotarget
Sébastien Corre, Nina Tardif, Nicolas Mouchet, Héloïse M Leclair, Lise Boussemart, Arthur Gautron, Laura Bachelot, Anthony Perrot, Anatoly Soshilov, Aljosja Rogiers, Florian Rambow, Erwan Dumontet, Karin Tarte, Alban Bessede, Gilles J Guillemin, Jean-Christophe Marine, Michael S Denison, David Gilot, Marie-Dominique Galibert
BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes...
November 14, 2018: Nature Communications
Greta Del Mistro, Philippe Lucarelli, Ines Müller, Sébastien De Landtsheer, Anna Zinoveva, Meike Hutt, Martin Siegemund, Roland E Kontermann, Stefan Beissert, Thomas Sauter, Dagmar Kulms
Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mut BRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network...
2018: NPJ Systems Biology and Applications
Sunilkumar Kakadia, Naveen Yarlagadda, Ramez Awad, Madappa Kundranda, Jiaxin Niu, Boris Naraev, Lida Mina, Tomislav Dragovich, Mark Gimbel, Fade Mahmoud
Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAF V600 -mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest...
2018: OncoTargets and Therapy
Michael J Vido, Kaitlyn Le, Edward J Hartsough, Andrew E Aplin
Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E ΔEx) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E ΔEx confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E ΔEx dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E ΔEx association with its substrate, MEK, is enhanced and required for RAF inhibitor resistance. RAF inhibitor treatment increased phosphorylation at serine 729 (S729) in BRAF V600E ΔEx...
November 6, 2018: Cell Reports
Nian Liu, Kuan Song Wang, Min Qi, Ying Jun Zhou, Guang Yao Zeng, Juan Tao, Jian Da Zhou, Jiang Lin Zhang, Xiang Chen, Cong Peng
BACKGROUND: Vitex negundo L (Verbenaceae) is an aromatic shrub that is abundant in Asian countries. A series of compounds from Vitex negundo have been used in traditional Chinese medicine for the treatment of various diseases. Cutaneous melanoma is one of the most aggressive malignancies. A significant feature of melanoma is its resistance to traditional chemotherapy and radiotherapy; therefore, there is an urgent need to develop novel treatments for melanoma. METHODS: We first examined the effects of VB1 (vitexin compound 1) on cell viability by CCK-8 (cell counting kit) and Colony Formation Assay; And then, we analyzed the apoptosis and cell cycle by flow cytometry, verified apoptosis by Immunoblotting...
November 6, 2018: Journal of Experimental & Clinical Cancer Research: CR
Steve Wagner, Georgios Vlachogiannis, Alexis De Haven Brandon, Melanie Valenti, Gary Box, Liam Jenkins, Caterina Mancusi, Annette Self, Floriana Manodoro, Ioannis Assiotis, Penny Robinson, Ritika Chauhan, Alistair G Rust, Nik Matthews, Kate Eason, Khurum Khan, Naureen Starling, David Cunningham, Anguraj Sadanandam, Clare M Isacke, Vladimir Kirkin, Nicola Valeri, Steven R Whittaker
Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines...
October 23, 2018: Oncogene
Julia K Tietze, Andrea Forschner, Carmen Loquai, Heidrun Mitzel-Rink, Lisa Zimmer, Frank Meiss, David Rafei-Shamsabadi, Jochen Utikal, Maike Bergmann, Friedegund Meier, Nicole Kreuzberg, Max Schlaak, Carsten Weishaupt, Claudia Pföhler, Mirjana Ziemer, Michael Fluck, Jessica Rainer, Markus V Heppt, Carola Berking
BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition. Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9...
September 28, 2018: Oncotarget
S Verykiou, M Alexander, N Edwards, R Plummer, B Chaudhry, P E Lovat, D S Hill
BACKGROUND: Patients with malignant melanoma often relapse following treatment with BRAF and/or MEK inhibitors (MEKi) due to development of drug resistance by melanoma subpopulations, mediated through induction of generic survival mechanisms. OBJECTIVES: The aim of this study was to establish the temporal pattern of CD271 regulation (a stem cell marker that mediates tumour aggressiveness) during development of resistance by melanoma to the MEKi trametinib, and to determine the association between development of resistance to trametinib and induction of pro-survival autophagy...
October 19, 2018: British Journal of Dermatology
Carla Daniela Robles-Espinoza
Drug resistance is a major problem in cancer treatment. In cutaneous melanoma, a large fraction of tumours carry BRAFV 600E or BRAFV 600K mutations (hereinafter referred to as BRAFV 600E/K ), which result in activation of the mitogen-activated protein kinase (MAPK) pathway, sustaining cancer cell proliferation and survival. In 2011, a landmark phase III study demonstrated that vemurafenib, a drug specifically targeting cells with BRAFV 600E mutations, significantly improved progression-free survival over the conventional chemotherapy drug dacarbazine (Chapman et al...
October 19, 2018: Pigment Cell & Melanoma Research
M Oellerich, E Schütz, J Beck, P D Walson
Genomic analyses in oncologic care allow for the development of more precise clinical laboratory tests that will be critical for personalized pharmacotherapy. Traditional biopsy-based approaches are limited by the availability of sequential tissue specimens to detect resistance. Blood-based genomic profiling ("liquid biopsy") is useful for longitudinal monitoring of tumor genomes and can complement biopsies. Tumor-associated mutations can be identified in cell-free tumor DNA (ctDNA) from patient blood samples and used for monitoring disease activity...
October 16, 2018: Therapeutic Drug Monitoring
Kai Wang, Yanrong Li, Na Song, Xiaofang Che, Kezuo Hou, Ling Xu, Ming Bai, Qiwei Wang, Yuanhe Wang, Yang Zhou, Meihui Cao, Yunpeng Liu, Jingdong Zhang
The BRAFV600E inhibitor vemurafenib is widely used to treat melanomas harboring the activated BRAFV600E mutation; however, vemurafenib showed poor efficacy in colon cancer, which impeded its clinical application for colon cancer patients with this mutation. The specific mechanism of vemurafenib resistance is not clear in colon cancer. In this study, we demonstrated that signal transducer and activator of transcription 3 (STAT3) activation influenced vemurafenib sensitivity in BRAFV600E mutant colon cancer cells...
October 15, 2018: Journal of Cellular Biochemistry
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