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Melanoma braf resistance

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
Tomoko Takahashi, Naoko Abe, Hiroyuki Kanoh, Yoshiko Banno, Mariko Seishima
Vemurafenib, a selective inhibitor of mutated BRAF, is used to treat late‑stage melanoma. However, resistance to vemurafenib is urgently required as it can have fatal consequences. Fingolimod (FTY720), a sphingosine‑1‑phosphate receptor modulator, has been used for the treatment of several malignant neoplasms in clinical trials. The present study investigated the effects of FTY720 and vemurafenib combination treatment on cell death induction, and defined the molecular mechanisms in vemurafenib‑resistant melanoma cells...
October 8, 2018: Molecular Medicine Reports
Aman Sharma, Rinkle Rani
Combination drug therapy is considered a better treatment option for various diseases, such as cancer, HIV, hypertension, and infections as compared to targeted drug therapies. Combination or synergism helps to overcome drug resistance, reduction in drug toxicity and dosage. Considering the complexity and heterogeneity among cancer types, drug combination provides promising treatment strategy. Increase in drug combination data raises a challenge for developing a computational approach that can effectively predict drugs synergism...
June 28, 2018: Journal of Bioinformatics and Computational Biology
Sana Sarvi, Richard Crispin, Yuting Lu, Lifan Zeng, Thomas D Hurley, Douglas R Houston, Alex von Kriegsheim, Che-Hong Chen, Daria Mochly-Rosen, Marco Ranzani, Marie E Mathers, Xiaowei Xu, Wei Xu, David J Adams, Neil O Carragher, Mayumi Fujita, Lynn Schuchter, Asier Unciti-Broceta, Valerie G Brunton, E Elizabeth Patton
5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance...
September 25, 2018: Cell Chemical Biology
Jun-Ho Ahn, Sung-Hee Hwang, Hyun-Soo Cho, Michael Lee
Melanoma cells have been shown to respond to BRAF inhibitors; however, intrinsic and acquired resistance limits their clinical application. In this study, we performed RNA-Seq analysis with BRAF inhibitor-sensitive (A375P) and -resistant (A375P/Mdr with acquired resistance and SK-MEL-2 with intrinsic resistance) melanoma cell lines, to reveal the genes and pathways potentially involved in intrinsic and acquired resistance to BRAF inhibitors. A total of 546 differentially expressed genes (DEGs), including 239 up-regulated and 307 down-regulated genes, were identified in both intrinsic and acquired resistant cells...
October 4, 2018: Biomolecules & Therapeutics
Giulia Cesi, Demetra Philippidou, Ines Kozar, Yeoun Jin Kim, Francois Bernardin, Guillaume Van Niel, Anke Wienecke-Baldacchino, Paul Felten, Elisabeth Letellier, Sonja Dengler, Dorothee Nashan, Claude Haan, Stephanie Kreis
BACKGROUND: Drug resistance remains an unsolved clinical issue in oncology. Despite promising initial responses obtained with BRAF and MEK kinase inhibitors, resistance to treatment develops within months in virtually all melanoma patients. METHODS: Microarray analyses were performed in BRAF inhibitor-sensitive and resistant cell lines to identify changes in the transcriptome that might play a role in resistance. siRNA approaches and kinase inhibitors were used to assess the involvement of the identified Anaplastic Lymphoma Kinase (ALK) in drug resistance...
October 5, 2018: Molecular Cancer
Lindsey Broussard, Amanda Howland, Sunhyo Ryu, Kyungsup Song, David Norris, Cheryl A Armstrong, Peter I Song
Over recent years, several new molecular and immunogenic therapeutic approaches to melanoma treatment have been approved and implemented in clinical practice. Mechanisms of resistance to these new therapies have become a major problem. Mutation-specific pharmacotherapy can result in simultaneous emergence of resistant clones at many separate body sites despite an initially positive therapeutic response. Additionally, treatments aimed at inducing apoptosis are subject to resistance due to escape through other known mechanisms of regulated cell death (RCD)...
September 2018: Chonnam Medical Journal
Nicholas Theodosakis, Casey G Langdon, Goran Micevic, Irina Krykbaeva, Robert E Means, David F Stern, Marcus W Bosenberg
This study evaluates the use of HMG-CoA reducatase inhibitors, or statins, as an adjunctive to BRAF and MEK inhibition as a treatment in melanomas and other tumors with driver mutations in the MAPK pathway. Experiments used simvastatin in conjunction with vemurafenib and selumetinib in vitro and simvastatin with vemurafenib in vivo to demonstrated additional growth abrogation beyond MAPK blockade alone. Additional studies demonstrated that statin anti-tumor effects appeared to depend on inhibition of isoprenoid synthesis given rescue with add-back of downstream metabolites...
October 3, 2018: Pigment Cell & Melanoma Research
Michael P Smith, Sareena Rana, Jennifer Ferguson, Emily J Rowling, Keith T Flaherty, Jennifer A Wargo, Richard Marais, Claudia Wellbrock
The BRAF-kinase and the MAPK-pathway are targets of current melanoma therapies. However, MAPK-pathway inhibition results in dynamic changes of down-stream targets that can counteract inhibitor-action not only during treatment, but also in acquired resistant tumours. One such dynamic change involves the expression of the transcription factor MITF, a crucial regulator of cell survival and proliferation in untreated as well as drug-addicted acquired resistant melanoma. Tight control over MITF expression levels is required for optimal melanoma growth, and while it is well established that the MAPK-pathway regulates MITF expression, the actual mechanism is insufficiently understood...
October 1, 2018: Pigment Cell & Melanoma Research
Ahmad Tarhini, Ragini R Kudchadkar
The treatment armamentarium for patients with metastatic melanoma has increased substantially over the past decade with the regulatory approval of targeted BRAF + MEK inhibitors and immune checkpoint inhibitors, which have vastly improved long-term outcomes. Recently, these advances have been rapidly translated to the high-risk adjuvant setting. Primary and acquired resistance to both immune and molecularly targeted agents, however, remains a challenge. Therefore, biomarkers predictive of response to therapy that can be assessed prior to initiation of treatment and early during the course of therapy are critical...
September 21, 2018: Cancer Treatment Reviews
Stefania Maraka, Filip Janku
Primary brain tumors can harbor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene alterations. BRAF is a serine/threonine kinase protein and is a downstream effector of the Ras-Raf-MEK extracellular signal-regulated kinase (ERK) signaling pathway, which is responsible for cell division and differentiation. BRAF-V600E mutations are most commonly found in pleomorphic xanthoastrocytoma, ganglioglioma, epithelioid glioblastoma, and gliomas diagnosed at a younger age; BRAF-KIAA1549 fusion is the most common BRAF alteration in pilocytic astrocytoma...
August 2018: Discovery Medicine
Azad Saei, Pieter Johan Adam Eichhorn
Response to targeted therapies is limited by the activation or inhibition of feedback loops. Here we report the ubiquitin specific peptidase 28/F-box WD repeat-containing protein 7 (USP28/FBW7) complex functions as a negative regulator of mitogen-activated protein kinase (MAPK) pathway by targeting v-raf murine sarcoma viral oncogene homolog B (BRAF) for degradation, a process which is lost in a large proportion of BRAF mutant melanoma patients, resulting in resistance to BRAF inhibitor therapies.
2018: Molecular & Cellular Oncology
Luigi Fattore, Ciro Francesco Ruggiero, Maria Elena Pisanu, Domenico Liguoro, Andrea Cerri, Susan Costantini, Francesca Capone, Mario Acunzo, Giulia Romano, Giovanni Nigita, Domenico Mallardo, Concetta Ragone, Maria Vincenza Carriero, Alfredo Budillon, Gerardo Botti, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto
Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma. Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease. Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients. We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis...
September 25, 2018: Cell Death and Differentiation
Kotryna Seip, Kjetil Jørgensen, Marco Vincent Haselager, Marco Albrecht, Mads Haugland Haugen, Eivind Valen Egeland, Philippe Lucarelli, Olav Engebraaten, Thomas Sauter, Gunhild Mari Mælandsmo, Lina Prasmickaite
Cancer cells' phenotypic plasticity, promoted by stromal cells, contributes to intra-tumoral heterogeneity and affects response to therapy. We have disclosed an association between fibroblast-stimulated phenotype switching and resistance to the clinically used BRAF inhibitor (BRAFi) vemurafenib in malignant melanoma, revealing a challenge in targeting the fibroblast-induced phenotype. Here we compared molecular features and drug sensitivity in melanoma cells grown as co-cultures with fibroblasts versus mono-cultures...
September 18, 2018: Cancer Letters
Mal Irvine, Ashleigh Stewart, Bernadette Pedersen, Suzanah Boyd, Richard Kefford, Helen Rizos
Nearly all patients with BRAF-mutant melanoma will progress on BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy within the first year of therapy. In the vast majority of progressing melanomas, resistance occurs via the re-activation of MAPK signalling, commonly via alterations in BRAF, NRAS and MEK1/2. A small proportion of resistant melanomas rely on the activation of the compensatory PI3K/AKT signalling cascade, although activation of this pathway does not preclude patient responses to BRAF/MEK inhibition...
September 20, 2018: Oncogenesis
Johannes Grimm, Anita Hufnagel, Marion Wobser, Andreas Borst, Sebastian Haferkamp, Roland Houben, Svenja Meierjohann
Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e...
September 20, 2018: Oncogenesis
Marianna Vitiello, Romina D'Aurizio, Laura Poliseno
In this short report, we pinpoint some technical and conceptual flaws that we found in the article entitled "miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma" (Díaz-Martínez et al., Cancer Research 2018). We also discuss how, in our opinion, these flaws led Díaz-Martínez and colleagues to incorrect conclusions about the biological role that miR-204 and miR-211 play in melanoma and about the terms of their involvement in the phenomenon of resistance to BRAF inhibitors...
July 2018: Oncoscience
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