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Melanoma braf resistance

Jia-Fang Liu, Kuang Chi Lai, Shu-Fen Peng, Pornsuda Maraming, Yi-Ping Huang, An-Cheng Huang, Fu-Shin Chueh, Wen-Wen Huang, Jing-Gung Chung
Many studies have demonstrated that berberine inhibited the cell migration and invasion in human cancer cell lines. However, the exact molecular mechanism of berberine inhibiting the cell migration and invasion of human melanoma A375.S2 and A375.S2/PLX (PLX4032 induced resistant A375.S2) skin cancer cells remains unknown. In this study, we investigated the anti-metastasis mechanisms of berberine in human melanoma cancer A375.S2 cells and A375.S2/PLX resistant cells in vitro. Berberine at low concentrations (0, 1, 1...
August 13, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Bor-Jang Hwang, Gautam Adhikary, Richard L Eckert, A-Lien Lu
Melanoma patients respond poorly to chemotherapies because they acquire drug resistance. Therapies that can overcome the resistance to inhibitors of the mutated BRAF protein kinase in melanoma are urgently needed. Chk1 protein kinase is a central component of the DNA damage response and plays a crucial role in controlling cell cycle progression. Analyses indicate that low mRNA expression of Chk1 is significantly associated with good overall survival of melanoma patients. To evaluate the effectiveness of Chk1 inhibitors in melanoma therapy, we have generated BRAF inhibitor (PLX4032 or vemurafenib) resistant melanoma cell lines (A375-PLX-R and WM9-PLX-R) from A375 and WM9, respectively...
July 13, 2018: Oncotarget
Nausicaa Malissen, Jean-Jacques Grob
The prognosis of patients with metastatic melanoma has dramatically improved in recent years with the introduction of two new therapeutic strategies. BRAF and MEK inhibitors are small molecules that are able to block the mitogen-activated protein kinase (MAPK) pathway, which is constitutively activated by recurrent BRAF V600 mutations in 45% of melanoma patients. These agents were shown to provide a rapid and strong response but are often limited by a high rate of secondary resistance. Monoclonal antibodies against the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) can restore an efficient and durable anti-tumor immunity, even following treatment discontinuation...
August 10, 2018: Drugs
Lee S Gottesdiener, Shannon O'Connor, Klaus J Busam, Helen Won, David B Solit, David M Hyman, Alexander N Shoushtari
PURPOSE: Patients with BRAF V600-wild type melanoma whose tumors progress on checkpoint inhibition currently have limited therapeutic options, and additional rational treatment targets are needed. ERBB2 alterations may be amenable to targeted inhibition, but the rate of ERBB2 alterations across melanoma subtypes is not well described. EXPERIMENTAL DESIGN: All patients with non-uveal melanoma (cutaneous, acral, mucosal, and unknown primary) whose tumors underwent multigene sequencing with MSK-IMPACT at Memorial Sloan Kettering Cancer Center from 2014-2018 were reviewed for known or likely oncogenic somatic alterations in ERBB2 and the other known canonical driver genes BRAF , NRAS , KIT , NF1 , GNAQ , and GNA11 Results: A patient with acral melanoma resistant to checkpoint inhibition was found to have an ERBB2 amplification and achieved a durable complete response to trastuzumab emtansine...
August 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Anupama Sahoo, Sanjaya K Sahoo, Piyush Joshi, Bongyong Lee, Ranjan J Perera
The clinical management of malignant melanoma remains a challenge because these tumors are intrinsically aggressive and prone to therapeutic resistance. Micro-RNA (miR)-211 is an emerging melanoma oncogene. Melanoma metabolism adapts to promote survival, including in response to BRAFV600E inhibition, but how miR-211 participates in this process is unknown. Here we generated miR-211 loss-of-function cell lines using CRISPR/Cas9 technology and show that miR-211 loss slowed growth and invasion in vitro, inhibited phosphoinositol-3-kinase (PI3K) signaling, and inhibited melanoma growth in vivo...
August 1, 2018: Journal of Investigative Dermatology
Yu-Jui Ho, Naishitha Anaparthy, David Molik, Grinu Mathew, Toby Aicher, Ami Patel, James Hicks, Molly Gale Hammell
Single-cell RNA-seq's (scRNA-seq) unprecedented cellular resolution at a genome-wide scale enables us to address questions about cellular heterogeneity that are inaccessible using methods that average over bulk tissue extracts. However, scRNA-seq data sets also present additional challenges such as high transcript dropout rates, stochastic transcription events, and complex population substructures. Here, we present a <u>s</u>ingle-cell RNA-seq <u>a</u>nalysis and <u>k</u>lustering <u>e</u>valuation (SAKE), a robust method for scRNA-seq analysis that provides quantitative statistical metrics at each step of the analysis pipeline...
July 30, 2018: Genome Research
Orsi Giricz, Yongkai Mo, Kimberly B Dahlman, Xiomaris M Cotto-Rios, Chiara Vardabasso, Hoa Nguyen, Bernice Matusow, Matthias Bartenstein, Veronika Polishchuk, Douglas B Johnson, Tushar D Bhagat, Rafe Shellooe, Elizabeth Burton, James Tsai, Chao Zhang, Gaston Habets, John M Greally, Yiting Yu, Paraic A Kenny, Gregg B Fields, Kith Pradhan, E Richard Stanley, Emily Bernstein, Gideon Bollag, Evripidis Gavathiotis, Brian L West, Jeffrey A Sosman, Amit K Verma
Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples. CSF1R was particularly elevated in melanomas with BRAF and other MAPK activating mutations...
July 25, 2018: JCI Insight
Ryan J Sullivan
Over the past 10 years of remarkable development of both molecularly targeted and immune-targeted therapy for the treatment of melanoma, a clear preference of immunotherapy over molecularly targeted therapy has emerged among melanoma treatment providers. Still, the clinical data remain remarkable for patients with BRAF-mutant stage III and IV melanoma, and there seems to be a clear benefit of BRAF-targeted therapy for these patients. The key, then, is to identify the best way to use BRAF-targeted therapy. In this review, the clinical data of molecular-targeted therapy are summarized, mechanisms of resistance to single-agent BRAF and combined BRAF with mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor are discussed, and strategies to overcome this resistance are presented; then, we review a number of clinical dilemmas that influence the decision-making of using targeted therapy over immunotherapy, and viceversa, and help define the specific role of targeted therapy in the immunotherapy era...
June 2018: Seminars in Cutaneous Medicine and Surgery
Tali Ofir Dovrat, Ethan Sokol, Garrett Frampton, Eliya Shachar, Sharon Pelles, Ravit Geva, Ido Wolf
INTRODUCTION: V600E BRAF mutation is an established driver mutation in a variety of tumors. Vemurafenib is a selective inhibitor of the BRAF V600E kinase, known to be highly effective in BRAF V600E-positive metastatic melanoma. As a single agent, vemurafenib is relatively ineffective in other V600E-positive malignancies. Case 1: A 72 year old man with metastatic CRC who failed several previous lines of chemotherapy. Genetic analysis of 315 cancer-related genes (Foundation Medicine, FMI) revealed a BRAF V600E mutation...
July 23, 2018: Cancer Biology & Therapy
Thein Swe, Kevin B Kim
Malignant melanoma is generally chemo- and radio-resistant, and patients with advanced melanoma have a poor prognosis. However, with our increased understanding of the checkpoint immune molecules and genetic alterations of melanoma cells, more effective immunotherapy, such as anti CTLA4 antibody and anti PD-1 antibodies, and targeted drug therapy, such as BRAF inhibitors and MEK inhibitors, have been developed, resulting in improved overall survival and quality of life of patients with advanced melanoma. In addition, emerging technologies to develop prognostic and predictive biomarkers for response to systemic therapy could help clinicians make more accurate assessments of the disease and formulate more effective treatment plans...
July 17, 2018: Clinical & Experimental Metastasis
Florian Rambow, Aljosja Rogiers, Oskar Marin-Bejar, Sara Aibar, Julia Femel, Michael Dewaele, Panagiotis Karras, Daniel Brown, Young Hwan Chang, Maria Debiec-Rychter, Carmen Adriaens, Enrico Radaelli, Pascal Wolter, Oliver Bechter, Reinhard Dummer, Mitchell Levesque, Adriano Piris, Dennie T Frederick, Genevieve Boland, Keith T Flaherty, Joost van den Oord, Thierry Voet, Stein Aerts, Amanda W Lund, Jean-Christophe Marine
Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment...
July 6, 2018: Cell
Xiaohui Wang, Huajun Qu, Yinghe Dong, Guozhi Wang, Yuchen Zhen, Pengsu Yi
Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. To define molecular mechanisms of vemurafenib resistance, we generated A375-R, WM35-R cell lines resistant to vemurafenib and show that the phosphorylated (p)-STAT3 was upregulated in these cells in vitro and in vivo. In particular, activation of the Signal-transducer-and-activator-of-transcription 3 (STAT3) pathway was associated with vemurafenib resistance...
June 28, 2018: Cancer Biomarkers: Section A of Disease Markers
Manfred Kunz, Henry Löffler-Wirth, Michael Dannemann, Edith Willscher, Gero Doose, Janet Kelso, Tina Kottek, Birgit Nickel, Lydia Hopp, Jenny Landsberg, Steve Hoffmann, Thomas Tüting, Paola Zigrino, Cornelia Mauch, Jochen Utikal, Mirjana Ziemer, Hans-Joachim Schulze, Michael Hölzel, Alexander Roesch, Susanne Kneitz, Svenja Meierjohann, Anja Bosserhoff, Hans Binder, Manfred Schartl
Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-seq analysis of laser-microdissected melanocytic nevi (n = 23) and primary melanoma samples (n = 57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering, and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2)...
July 11, 2018: Oncogene
Jeffrey A Knauf, Kathleen A Luckett, Kuen-Yuan Chen, Francesca Voza, Nicholas D Socci, Ronald Ghossein, James A Fagin
Anaplastic thyroid carcinomas (ATC) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in non-melanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment...
July 10, 2018: Journal of Clinical Investigation
Ryan J Sullivan
Targeting BRAF in BRAF-mutant melanoma is highly effective, but most patients develop resistance. Heat shock protein 90 (HSP90) has been implicated and identified as a therapeutic target. Ultimately, early stage clinical investigation will be necessary to provide proof-of-principle of this approach, and if appropriate randomized trials to confirm promising findings.
July 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sara Alavi, Ashleigh Jacqueline Stewart, Richard F Kefford, Su Yin Lim, Elena Shklovskaya, Helen Rizos
Immune checkpoint inhibitors that block the programmed cell death protein 1/PD-L1 pathway have significantly improved the survival of patients with advanced melanoma. Immunotherapies are only effective in 15-40% of melanoma patients and resistance is associated with defects in antigen presentation and interferon signaling pathways. In this study, we examined interferon-γ (IFNγ) responses in a large panel of immune checkpoint inhibitor-naïve melanoma cells with defined genetic drivers; BRAF -mutant ( n  = 11), NRAS -mutant ( n  = 10), BRAF/NRAS wild type ( n  = 10), and GNAQ/GNA11 -mutant uveal melanomas (UVMs) ( n  = 8)...
2018: Frontiers in Immunology
Tiziana Notarangelo, Lorenza Sisinni, Stefania Trino, Giovanni Calice, Vittorio Simeon, Matteo Landriscina
Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 26-53% of human thyroid malignancies and, differently from melanomas, are poorly sensitive to BRAF inhibitors (BRAFi), and develop acquired resistance through activation of alternative signaling pathways. A whole-genome gene expression analysis of TC BRAF V600E cells exposed to PLX4032 identified JAK/STAT among the most significantly modulated signaling pathways. Interestingly, both transient exposure and chronic adaptation to PLX4032 resulted in upregulation of IL6/STAT3 axis and this impaired the cytostatic activity of PLX4032...
October 1, 2018: Cancer Letters
Federica Fratangelo, Rosa Camerlingo, Maria Vincenza Carriero, Giuseppe Pirozzi, Giuseppe Palmieri, Giusy Gentilcore, Concetta Ragone, Michele Minopoli, Paolo Antonio Ascierto, Maria Letizia Motti
Melanoma is a molecularly heterogeneous disease with many genetic mutations and altered signaling pathways. Activating mutations in the BRAF oncogene are observed in approximately 50% of cutaneous melanomas and the use of BRAF inhibitor (BRAFi) compounds has been reported to improve the outcome of patients with BRAF-mutated metastatic melanoma. However, the majority of these patients develop resistance within 6-8 months following the initiation of BRAFi treatment. In this study, we examined the possible use of the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, ABT-888 (veliparib), as a novel molecule that may be successfully employed in the treatment of BRAFi-resistant melanoma cells...
September 2018: International Journal of Oncology
Sabrina Rizzolio, Gabriella Cagnoni, Chiara Battistini, Stefano Bonelli, Claudio Isella, Jo A Van Ginderachter, René Bernards, Federica Di Nicolantonio, Silvia Giordano, Luca Tamagnone
Cancer cell dependence on activated oncogenes is targeted therapeutically, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF-inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in Neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene-inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases, EGFR or IGF1R, which in turn sustained cancer cell growth and mediated acquired resistance to BRAF, HER2, or MET inhibitors...
June 28, 2018: Journal of Clinical Investigation
Ali Talebi, Jonas Dehairs, Florian Rambow, Aljosja Rogiers, David Nittner, Rita Derua, Frank Vanderhoydonc, Joao A G Duarte, Francesca Bosisio, Kathleen Van den Eynde, Kris Nys, Mónica Vara Pérez, Patrizia Agostinis, Etienne Waelkens, Joost Van den Oord, Sarah-Maria Fendt, Jean-Christophe Marine, Johannes V Swinnen
Whereas significant anti-tumor responses are observed in most BRAFV600E -mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism, therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation...
June 27, 2018: Nature Communications
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