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https://www.readbyqxmd.com/read/29137417/inhibition-of-retinoic-acid-receptor-%C3%AE-signaling-confers-glycolytic-dependence-and-sensitization-to-dichloroacetate-in-melanoma-cells
#1
Cecilie Abildgaard, Christina Dahl, Ahmad Abdul-Al, Annette Christensen, Per Guldberg
Dysregulation of metabolism during melanoma progression is tightly associated with the acquisition of genetic and epigenetic alterations in regulators of metabolic pathways. Retinoic acid receptor beta (RARβ) is epigenetically silenced in a large proportion of melanomas, but a link between RARβ and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RARβ agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARβ led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29033690/dual-egfr-and-braf-blockade-overcomes-resistance-to-vemurafenib-in-braf-mutated-thyroid-carcinoma-cells
#2
Tiziana Notarangelo, Lorenza Sisinni, Valentina Condelli, Matteo Landriscina
BACKGROUND: BRAF inhibitors are effective anticancer agents in BRAF-mutated melanomas. By contrast, evidences about sensitivity of thyroid carcinomas to BRAF inhibition are conflicting and it has been proposed that BRAF V600E thyroid carcinoma cells are less sensitive to BRAF inhibitors due to activation of parallel signaling pathways. This study evaluated the hypothesis that feedback activation of EGFR signaling counteracts the cytostatic activity of vemurafenib (PLX4032) in BRAF V600E thyroid carcinoma cells...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28708099/role-played-by-signalling-pathways-in-overcoming-braf-inhibitor-resistance-in-melanoma
#3
REVIEW
Xian Yang Chan, Alamdeep Singh, Narin Osman, Terrence J Piva
The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28513992/immunoregulatory-protein-b7-h3-promotes-growth-and-decreases-sensitivity-to-therapy-in-metastatic-melanoma-cells
#4
Karine Flem-Karlsen, Christina Tekle, Yvonne Andersson, Kjersti Flatmark, Øystein Fodstad, Caroline E Nunes-Xavier
B7-H3 (CD276) belongs to the B7 family of immunoregulatory proteins and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK) and AKT/mTOR pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor), and triciribidine (API-2; AKT inhibitor)...
September 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28188228/time-resolved-phosphoproteome-analysis-of-paradoxical-raf-activation-reveals-novel-targets-of-erk
#5
Peter Kubiniok, Hugo Lavoie, Marc Therrien, Pierre Thibault
Small molecules targeting aberrant RAF activity, like vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream "paradoxical" ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to vemurafenib...
April 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28098866/in-vitro-long-term-treatment-with-mapk-inhibitors-induces-melanoma-cells-with-resistance-plasticity-to-inhibitors-while-retaining-sensitivity-to-cd8-t-cells
#6
Florencia Paula Madorsky Rowdo, Antonela Barón, Erika María von Euw, José Mordoh
The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of long‑term in vitro treatment of two different V600E BRAF‑mutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR)...
March 2017: Oncology Reports
https://www.readbyqxmd.com/read/28093487/a-pilot-trial-of-the-combination-of-vemurafenib-with-adoptive-cell-therapy-in-patients-with-metastatic-melanoma
#7
Drew C Deniger, Mei Li M Kwong, Anna Pasetto, Mark E Dudley, John R Wunderlich, Michelle M Langhan, Chyi-Chia Richard Lee, Steven A Rosenberg
PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF(V600) mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration...
January 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28056412/toxicity-of-concurrent-stereotactic-radiotherapy-and-targeted-therapy-or-immunotherapy-a-systematic-review
#8
REVIEW
Stephanie G C Kroeze, Corinna Fritz, Morten Hoyer, Simon S Lo, Umberto Ricardi, Arjun Sahgal, Rolf Stahel, Roger Stupp, Matthias Guckenberger
BACKGROUND AND PURPOSE: Both stereotactic radiotherapy (SRT) and immune- or targeted therapy play an increasingly important role in personalized treatment of metastatic disease. Concurrent application of both therapies is rapidly expanding in daily clinical practice. In this systematic review we summarize severe toxicity observed after concurrent treatment. MATERIAL AND METHODS: PubMed and EMBASE databases were searched for English literature published up to April 2016 using keywords "radiosurgery", "local ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab", "cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib", "sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab", "nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib", "trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK"...
February 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28026115/immune-cell-mediated-biodegradable-theranostic-nanoparticles-for-melanoma-targeting-and-drug-delivery
#9
Zhiwei Xie, Yixue Su, Gloria B Kim, Erhan Selvi, Chuying Ma, Virginia Aragon-Sanabria, Jer-Tsong Hsieh, Cheng Dong, Jian Yang
Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell-mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer-specific drug delivery...
March 2017: Small
https://www.readbyqxmd.com/read/28001152/peg-peptide-hydrogels-reveal-differential-effects-of-matrix-microenvironmental-cues-on-melanoma-drug-sensitivity
#10
Emi Y Tokuda, Caitlin E Jones, Kristi S Anseth
Metastatic melanoma is highly drug resistant, though the exact mechanisms of this resistance are not completely understood. One method to study melanoma drug responsiveness in vitro is through the use of multicellular spheroids, which have been found to exhibit decreased drug sensitivity compared to traditional 2D culture on various substrates. Because it is unclear whether dimensionality, cell-matrix interactions, and/or cell-cell contacts may influence melanoma drug responsiveness, we utilized a synthetic PEG-based hydrogel to compare the responses of cells cultured on top of or encapsulated within matrices with the same adhesive ligand density, polymer density, and material properties...
January 23, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/27880942/acquired-resistance-to-braf-inhibition-induces-epithelial-to-mesenchymal-transition-in-braf-v600e-mutant-thyroid-cancer-by-c-met-mediated-akt-activation
#11
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...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27786591/suppression-of-b-raf-v600e-melanoma-cell-survival-by-targeting-mitochondria-using-triphenyl-phosphonium-conjugated-nitroxide-or-ubiquinone
#12
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)...
February 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/27689874/hepatocyte-growth-factor-renders-braf-mutant-human-melanoma-cell-lines-resistant-to-plx4032-by-downregulating-the-pro-apoptotic-bh3-only-proteins-puma-and-bim
#13
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
https://www.readbyqxmd.com/read/27563819/cytokines-can-counteract-the-inhibitory-effect-of-mek-i-on-nk-cell-function
#14
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...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27222248/paradoxical-activation-of-mek-erk-signaling-induced-by-b-raf-inhibition-enhances-dr5-expression-and-dr5-activation-induced-apoptosis-in-ras-mutant-cancer-cells
#15
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
https://www.readbyqxmd.com/read/27087167/role-of-the-protein-kinase-braf-in-the-pathogenesis-of-endometriosis
#16
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
https://www.readbyqxmd.com/read/26984758/hsp70-inhibition-limits-fak-dependent-invasion-and-enhances-the-response-to-melanoma-treatment-with-braf-inhibitors
#17
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
https://www.readbyqxmd.com/read/26684239/overcoming-melanoma-resistance-to-vemurafenib-by-targeting-ccl2-induced-mir-34a-mir-100-and-mir-125b
#18
COMPARATIVE STUDY
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
https://www.readbyqxmd.com/read/26640592/plx4032-mediated-melanoma-associated-antigen-potentiation-in-patient-derived-primary-melanoma-cells
#19
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
https://www.readbyqxmd.com/read/26456083/c-met-mediated-reactivation-of-pi3k-akt-signaling-contributes-to-insensitivity-of-braf-v600e-mutant-thyroid-cancer-to-braf-inhibition
#20
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
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