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Hyung Kwon Byeon, Hwi Jung Na, Yeon Ju Yang, Sooah Ko, Sun Och Yoon, Minhee Ku, Jaemoon Yang, Jae Wook Kim, Myung Jin Ban, Ji-Hoon Kim, Da Hee Kim, Jung Min Kim, Eun Chang Choi, Chang-Hoon Kim, Joo-Heon Yoon, Yoon Woo Koh
Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy...
November 21, 2016: Oncotarget
Seung-Keun Hong, Dmytro Starenki, Pui-Kei Wu, Jong-In Park
Most BRAF-mutated melanomas initially responsive to the FDA-approved inhibitors preferentially targeting B-Raf mutated in Val600 residue eventually relapse, requiring additional therapeutic modalities. Recent studies report the significance of metabolic reprograming in mitochondria for maintenance of BRAF-mutated melanomas and for development of their drug resistance to B-Raf inhibitors, providing a rationale for targeting mitochondria as a potential therapeutic strategy for melanoma. We therefore determined whether mitochondria-targeted metabolism-interfering agents can effectively suppress human B-Raf(V600E) melanoma cell lines and their dabrafenib/PLX4032-resistant progenies using mitochondria-targeted carboxy-proxyl (Mito-CP) and ubiquinone (Mito-Q)...
October 27, 2016: Cancer Biology & Therapy
Leona Rohrbeck, Jia-Nan Gong, Erinna F Lee, Andrew J Kueh, Andreas Behren, Lin Tai, Guillaume Lessene, David C S Huang, Walter D Fairlie, Andreas Strasser, Marco J Herold
A large proportion of melanomas harbour the activating BRAF(V600E) mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAF(V600E) kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM...
December 2016: Cell Death and Differentiation
Claudia Manzini, Roberta Venè, Irene Cossu, Marina Gualco, Simonetta Zupo, Mariella Dono, Francesco Spagnolo, Paola Queirolo, Lorenzo Moretta, Maria Cristina Mingari, Gabriella Pietra
Oncogene-targeted therapies based on mutated BRAF- and/or MEK-specific inhibitors have been developed for melanoma treatment. Although these drugs induce tumor regression in a high percentage of patients, clinical responses are frequently limited in time and tumors often recur. Recent studies suggested that the combination of BRAF/MEK inhibition with immunotherapy could represent a promising strategy for the cure of melanoma. NK cells are suitable effectors for tumor immunotherapy. Here we show that PLX4032 (a mutant BRAFV600 inhibitor) had no effect on the functional properties of NK cells cultured in the presence of IL-2 or IL-15...
August 22, 2016: Oncotarget
You-Take Oh, Jiusheng Deng, Ping Yue, Shi-Yong Sun
B-Raf inhibitors have been used for the treatment of some B-Raf-mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. This study focused on determining the effects of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells...
2016: Scientific Reports
Pietro Santulli, Louis Marcellin, Sandrine Chouzenoux, Veronique Boulard, Pierre-Alexandre Just, Carole Nicco, Christiane Chereau, Claudia Tosti, Charles Chapron, Frédéric Batteux
OBJECTIVE: Mitogen-activated protein kinases (MAPKs) are involved in the proliferation and survival of endometriotic lesions. Vemurafenib (PLX4032) is a novel protein kinase inhibitor that targets BRAF, a member of the MAPK pathway. The present study tested the in vitro and in vivo effects of PLX4032 on endometriotic cells. RESEARCH DESIGN AND METHODS: We conducted a laboratory study in a tertiary-care university hospital from January 2013 to September 2013. We enrolled a cohort of 40 patients: 20 with histologically proven endometriosis and 20 unaffected women...
August 2016: Expert Opinion on Therapeutic Targets
Anna Budina-Kolomets, Marie R Webster, Julia I-Ju Leu, Matthew Jennis, Clemens Krepler, Anastasia Guerrini, Andrew V Kossenkov, Wei Xu, Giorgos Karakousis, Lynn Schuchter, Ravi K Amaravadi, Hong Wu, Xiangfan Yin, Qin Liu, Yiling Lu, Gordon B Mills, Xiaowei Xu, Donna L George, Ashani T Weeraratna, Maureen E Murphy
The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients...
May 1, 2016: Cancer Research
Elisabetta Vergani, Lorenza Di Guardo, Matteo Dugo, Sara Rigoletto, Gabrina Tragni, Roberta Ruggeri, Federica Perrone, Elena Tamborini, Annunziata Gloghini, Flavio Arienti, Barbara Vergani, Paola Deho, Loris De Cecco, Viviana Vallacchi, Paola Frati, Eriomina Shahaj, Antonello Villa, Mario Santinami, Filippo De Braud, Licia Rivoltini, Monica Rodolfo
In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase...
January 26, 2016: Oncotarget
Andrea L George, Robert Suriano, Shilpi Rajoria, Maria C Osso, Neha Tuli, Elyse Hanly, Jan Geliebter, Angelo N Arnold, Marc Wallack, Raj K Tiwari
Over expression of various immunogenic melanoma associated antigens (MAAs) has been exploited in the development of immunotherapeutic melanoma vaccines. Expression of MAAs such as MART-1 and gp100 is modulated by the MAPK signaling pathway, which is often deregulated in melanoma. The protein BRAF, a member of the MAPK pathway, is mutated in over 60% of melanomas providing an opportunity for the identification and approval by the FDA of a small molecule MAPK signaling inhibitor PLX4032 that functions to inactivate mutant BRAF(V600E)...
2015: Journal of Cancer
Hyung Kwon Byeon, Hwi Jung Na, Yeon Ju Yang, Hyeong Ju Kwon, Jae Won Chang, Myung Jin Ban, Won Shik Kim, Dong Yeob Shin, Eun Jig Lee, Yoon Woo Koh, Joo-Heon Yoon, Eun Chang Choi
BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer is reported to be low. The purpose of this study is to investigate the resistance mechanism responsible for this low treatment response to BRAF inhibitor in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation...
November 2016: Molecular Carcinogenesis
F Kruiswijk, S C Hasenfuss, R Sivapatham, M P Baar, D Putavet, K A T Naipal, N J F van den Broek, W Kruit, P J van der Spek, D C van Gent, A B Brenkman, J Campisi, B M T Burgering, J H J Hoeijmakers, P L J de Keizer
Melanoma is the most lethal form of skin cancer and successful treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors only show a temporary benefit due to rapid occurrence of resistance, whereas immunotherapy is mainly effective in selected subsets of patients. Thus, there is a need to identify new targets to improve treatment of metastatic melanoma. To this extent, we searched for markers that are elevated in melanoma and are under regulation of potentially druggable enzymes. Here, we show that the pro-proliferative transcription factor FOXM1 is elevated and activated in malignant melanoma...
April 28, 2016: Oncogene
T Mahgoub, A J Eustace, D M Collins, N Walsh, N O'Donovan, J Crown
Despite recent advances in targeted therapies and immunotherapies metastatic melanoma remains only rarely curable. The objective of the present study was to identify novel therapeutic targets for metastatic melanoma. A library of 160 well-characterised and potent protein kinase inhibitors was screened in the BRAF mutant cell line Sk-Mel-28, and the NRAS mutant Sk-Mel-2, using proliferation assays. Of the 160 inhibitors tested, 20 achieved >50% growth inhibition in both cell lines. Six of the 20 were cyclin dependent kinase (CDK) inhibitors, including two CDK4 inhibitors...
September 2015: International Journal of Oncology
Yanling Li, Yuping Li, Qiang Liu, Aixue Wang
Melanoma is the deadliest form of skin cancer, and BRAFV600E is a driver mutation that promotes melanoma growth and survival. PLX4032 is the first effective compound in clinical use for the treatment of patients with mutant BRAFV600. However, resistance to PLX4032 develops quickly within months. Activation of a series of receptor tyrosine kinases, including the platelet-derived growth factor receptor (PDGFR), has been identified to be the underlying mechanism for development of resistance to PLX4032. In this work, we investigated the anticancer activity of tyrphostin AG1296, a PDGFR inhibitor, in melanoma, especially PLX4032-resistant melanoma...
2015: OncoTargets and Therapy
Molly H Jenkins, Walburga Croteau, David W Mullins, Constance E Brinckerhoff
Vertical growth phase (VGP) melanoma is frequently metastatic, a process mediated by changes in gene expression, which are directed by signal transduction pathways in the tumor cells. A prominent signaling pathway is the Ras-Raf-Mek-Erk MAPK pathway, which increases expression of genes that promote melanoma progression. Many melanomas harbor a mutation in this pathway, BRAF(V600E), which constitutively activates MAPK signaling and expression of downstream target genes that facilitate tumor progression. In BRAF(V600E) melanoma, the small molecule inhibitor, vemurafenib (PLX4032), has revolutionized therapy for melanoma by inducing rapid tumor regression...
October 2015: Matrix Biology: Journal of the International Society for Matrix Biology
Mitchell S Stark, Vanessa F Bonazzi, Glen M Boyle, Jane M Palmer, Judith Symmons, Catherine M Lanagan, Christopher W Schmidt, Adrian C Herington, Robert Ballotti, Pamela M Pollock, Nicholas K Hayward
To identify 'melanoma-specific' microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers...
July 10, 2015: Oncotarget
Stephen Mok, Jennifer Tsoi, Richard C Koya, Siwen Hu-Lieskovan, Brian L West, Gideon Bollag, Thomas G Graeber, Antoni Ribas
BACKGROUND: Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics. The production of colony stimulating factor 1 (CSF-1) in tumors recruits myeloid cells such as M2-polarized macrophages and myeloid derived suppressor cells (MDSC), leading to an immune suppressive tumor milieu. METHODS: We used the syngeneic mouse model of BRAF (V600E) -driven melanoma SM1, which secretes CSF-1, to evaluate the ability of the CSF-1 receptor (CSF-1R) inhibitor PLX3397 to improve the antitumor efficacy of the oncogenic BRAF inhibitor vemurafenib...
May 5, 2015: BMC Cancer
Jennifer L Leight, Emi Y Tokuda, Caitlin E Jones, Austin J Lin, Kristi S Anseth
Matrix metalloproteinases (MMPs) are important for many different types of cancer-related processes, including metastasis. Understanding the functional impact of changes in MMP activity during cancer treatment is an important facet not typically evaluated as part of preclinical research. With MMP activity being a critical component of the metastatic cascade, we designed a 3D hydrogel system to probe whether pharmacological inhibition affected human melanoma cell proteolytic activity; metastatic melanoma is a highly aggressive and drug-resistant form of skin cancer...
April 28, 2015: Proceedings of the National Academy of Sciences of the United States of America
Y-T Oh, J Deng, P Yue, T K Owonikoko, F R Khuri, S-Y Sun
Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy...
January 28, 2016: Oncogene
Scott A Stuart, Stephane Houel, Thomas Lee, Nan Wang, William M Old, Natalie G Ahn
Inhibitors of oncogenic B-RAF(V600E) and MKK1/2 have yielded remarkable responses in B-RAF(V600E)-positive melanoma patients. However, the efficacy of these inhibitors is limited by the inevitable onset of resistance. Despite the fact that these inhibitors target the same pathway, combination treatment with B-RAF(V600E) and MKK1/2 inhibitors has been shown to improve both response rates and progression-free survival in B-RAF(V600E) melanoma patients. To provide insight into the molecular nature of the combinatorial response, we used quantitative mass spectrometry to characterize the inhibitor-dependent phosphoproteome of human melanoma cells treated with the B-RAF(V600E) inhibitor PLX4032 (vemurafenib) or the MKK1/2 inhibitor AZD6244 (selumetinib)...
June 2015: Molecular & Cellular Proteomics: MCP
Alexander Plotnikov, Karen Flores, Galia Maik-Rachline, Eldar Zehorai, Einat Kapri-Pardes, Denise A Berti, Tamar Hanoch, Michal J Besser, Rony Seger
A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter...
2015: Nature Communications
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