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Melanoma braf resistance

Chi-Che Hsieh, Che-Hung Shen
Melanoma is the deadliest form of skin cancer worldwide. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to identify more effective therapeutic targets. Approximately, one half of advanced melanoma bears a mutation in the BRAF gene that makes BRAF as an important therapeutic target. Significant clinical benefit is associated with BRAF and MEK inhibitors (MAPKi) on targeting patients with BRAF V600 mutations. However, the frequent and rapid development of acquired resistance still is the major challenge facing the melanoma...
February 18, 2019: Current Treatment Options in Oncology
Cigdem Atay, Taekyoung Kwak, Sergio Lavilla-Alonso, Laxminarasimha Donthireddy, Allison D Richards, Valerie E Moberg, Shari Pilon-Thomas, Michael J Schell, Jane L Messina, Vito W Rebecca, Min Xiao, Jiufeng Tan, Gao Zhang, Jeffrey S Weber, Meenhard Herlyn, Amod A Sarnaik, Dmitry I Gabrilovich
PURPOSE: BRAF and MEK inhibitors (BRAFi, MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T cells therapy (ACT) in melanoma resistant to BRAFi. EXPERIMENTAL DESIGN: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as PDXs derived from patients...
February 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Biljana Cvetanova, Ya-Ching Shen, Lie-Fen Shyur
Mutated proto-oncogene BRAF is a bona fide therapeutic target for melanomas. Regrettably, melanoma acquires resistance to BRAF inhibitors, e.g., vemurafenib (PLX4032) casting doubt on this promising melanoma targeted therapy. In this study, we explored the bioactivity of triterpenoid saponin cumingianoside A (CUMA), isolated from leaves and twigs of Dysoxylum cumingianum against PLX4032-resistant BRAFV 600E mutant melanoma A375-R in vitro and in vivo . Our data show that CUMA treatment inhibited A375-R melanoma cell proliferation in a time- and dose-dependent manner...
2019: Frontiers in Pharmacology
István Szász, Viktória Koroknai, Tímea Kiss, Laura Vízkeleti, Róza Ádány, Margit Balázs
Selective inhibition of the mutant BRAF protein is a highly promising therapeutic approach for melanoma patients carrying the BRAF mutation. Despite the remarkable clinical response, most patients develop resistance and experience tumour regrowth. To clarify the molecular background of BRAF inhibitor resistance, we generated four drug-resistant melanoma cell lines from paired primary/metastatic cell lines using a vemurafenib analogue PLX4720. Three of the resistant cell lines showed decreased proliferation after drug withdrawal, but the proliferation of one cell line (WM278) increased notably...
February 6, 2019: Melanoma Research
Raimundo Gonçalves de Oliveira Júnior, Antoine Bonnet, Estelle Braconnier, Hugo Groult, Grégoire Prunier, Laureen Beaugeard, Raphäel Grougnet, Jackson Roberto Guedes da Silva Almeida, Christiane Adrielly Alves Ferraz, Laurent Picot
Cutaneous melanoma has a high capacity to metastasize and significant resistance to conventional therapeutic protocols, which makes its treatment difficult. The combination of conventional drugs with cytostatic molecules of low toxicity has been shown to be an interesting alternative for sensitization of tumor cells to chemotherapy. In this study, we evaluated the effect of bixin, an abundant apocarotenoid present in Bixa orellana, on the sensitization of human melanoma cells (A2058) to dacarbazine treatment, an anticancer agent clinically used for the therapy of metastatic melanoma...
February 7, 2019: Food and Chemical Toxicology
B Shannan, J Matschke, H Chauvistré, F Vogel, D Klein, F Meier, D Westphal, J Bruns, R Rauschenberg, J Utikal, A Forschner, C Berking, P Terheyden, E Dabrowski, R Gutzmer, D Rafei-Shamsabadi, F Meiss, L Heinzerling, L Zimmer, Elisabeth Livingstone, Renáta Váraljai, A Hoewner, S Horn, J Klode, M Stuschke, B Scheffler, A Marchetto, G Sannino, T G P Grünewald, D Schadendorf, V Jendrossek, A Roesch
INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases...
February 2, 2019: European Journal of Cancer
Jiaojiao Hao, Wenhua Fan, Yizhuo Li, Ranran Tang, Chunfang Tian, Qian Yang, Tianhua Zhu, Chaoliang Diao, Sheng Hu, Manyu Chen, Ping Guo, Qian Long, Changlin Zhang, Ge Qin, Wendan Yu, Miao Chen, Liren Li, Lijun Qin, Jingshu Wang, Xiuping Zhang, Yandong Ren, Penghui Zhou, Lijuan Zou, Kui Jiang, Wei Guo, Wuguo Deng
BACKGROUND: As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment. METHODS: Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice...
February 4, 2019: Journal of Experimental & Clinical Cancer Research: CR
Valentina Perotti, Paola Baldassari, Alessandra Molla, Gabriella Nicolini, Ilaria Bersani, Giulia Grazia, Fabio Benigni, Andrea Maurichi, Mario Santinami, Andrea Anichini, Roberta Mortarini
Discovery of new actionable targets and functional networks in melanoma is an urgent need as only a fraction of metastatic patients achieves durable clinical benefit by targeted therapy or immunotherapy approaches. Here we show that NFATc2 expression is associated with an EMT-like transcriptional program and with an invasive melanoma phenotype, as shown by analysis of melanoma cell lines at the mRNA and protein levels, interrogation of the TCGA melanoma dataset and characterization of melanoma lesions by immunohistochemistry...
February 1, 2019: Oncogene
Ophelia Maertens, Ryan Kuzmickas, Haley E Manchester, Chloe E Emerson, Alessandra G Gavin, Caroline J Guild, Terence C Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi A Garraway, Keith T Flaherty, Shailja Pathania, Stephen J Elledge, Karen Cichowski
While the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS- and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three Ras pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, both in models that are sensitive or relatively resistant to these agents...
February 1, 2019: Cancer Discovery
Kyoko Miyamoto, Masaaki Sawa
The BRAF inhibitors dabrafenib and vemurafenib induce remarkable clinical responses in patients with BRAF-mutated melanomas. However, adverse events, including the emergence of secondary tumors and drug resistance, have been reported. Studies have revealed that undesirable RAF dimerization induced by inhibitors promotes these adverse effects. Here, we developed highly sensitive biosensors of RAF dimerization in cells utilizing the split enhanced click beetle luciferase (Emerald Luc, ELuc) complementation technique...
January 24, 2019: Scientific Reports
Pietro Mancuso, Rossella Tricarico, Vikram Bhattacharjee, Laura Cosentino, Yuwaraj Kadariya, Jaroslav Jelinek, Emmanuelle Nicolas, Margret Einarson, Neil Beeharry, Karthik Devarajan, Richard A Katz, Dorjbal G Dorjsuren, Hongmao Sun, Anton Simeonov, Antonio Giordano, Joseph R Testa, Guillaume Davidson, Irwin Davidson, Lionel Larue, Robert W Sobol, Timothy J Yen, Alfonso Bellacosa
Melanoma is an aggressive neoplasm with increasing incidence that is classified by the NCI as a recalcitrant cancer, i.e., a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signaling pathway and immune checkpoints. As drug resistance remains a major obstacle to treatment success, advanced therapeutic approaches based on novel targets are still urgently needed. We reasoned that the base excision repair enzyme thymine DNA glycosylase (TDG) could be such a target for its dual role in safeguarding the genome and the epigenome, by performing the last of the multiple steps in DNA demethylation...
January 23, 2019: Oncogene
Haruka Goto, Takatoshi Shimauchi, Kensuke Fukuchi, Naoki Yokota, Shinichiro Koizumi, Masahiro Aoshima, Yuno Endo, Yurika Masuda, Hidehiko Miyazawa, Akira Kasuya, Katsumasa Nakamura, Taisuke Ito, Yoshiki Tokura
No abstract text is available yet for this article.
January 23, 2019: Acta Dermato-venereologica
Colette Moses, Fiona Nugent, Charlene Babra Waryah, Benjamin Garcia-Bloj, Alan R Harvey, Pilar Blancafort
PTEN expression is lost in many cancers, and even small changes in PTEN activity affect susceptibility and prognosis in a range of highly aggressive malignancies, such as melanoma and triple-negative breast cancer (TNBC). Loss of PTEN expression occurs via multiple mechanisms, including mutation, transcriptional repression and epigenetic silencing. Transcriptional repression of PTEN contributes to resistance to inhibitors used in the clinic, such as B-Raf inhibitors in BRAF mutant melanoma. We aimed to activate PTEN expression using the CRISPR system, specifically dead (d) Cas9 fused to the transactivator VP64-p65-Rta (VPR)...
December 14, 2018: Molecular Therapy. Nucleic Acids
Claudia Trojaniello, Lucia Festino, Vito Vanella, Paolo A Ascierto
Combination treatment with a BRAF inhibitor and MEK inhibitor is the standard of care for patients with advanced BRAFV600 mutation-positive melanoma. With the currently available combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib, median progression-free survival (PFS) of over 12 months has been achieved. However, treatment resistance and disease recurrence remain a clinical challenge. Areas covered: Encorafenib in combination with bimetinib offers a new approach that may offer benefits over existing BRAF/MEK inhibitor combinations...
January 17, 2019: Expert Review of Clinical Pharmacology
Steve Swenson, Catalina Silva-Hirschberg, Weijun Wang, Anupam Singh, Florence M Hofman, Kristen L Chen, Axel H Schönthal, Thomas C Chen
Despite new treatments introduced over the past several years, metastatic melanoma remains difficult to cure. Although melanoma in situ (MIS) has better prognosis, it relies heavily on thorough surgical excision, where ill-defined margins can pose a challenge to successful removal, potentially leading to invasive melanoma. As well, MIS in the head and neck area can create serious aesthetic concerns with regard to the surgical defect and substantial scar formation. Toward improved treatment of localized melanoma, including the targeting of unrecognized invasive components, we have been studying a novel agent, NEO412, designed for transdermal application...
December 11, 2018: Oncotarget
James L Figarola, Jyotsana Singhal, Sharad Singhal, Jyotirmoy Kusari, Arthur Riggs
BRAF mutations are detected in >50% of all melanomas. These mutations impair the LKB1-AMPK signaling, an important metabolic pathway associated with cell growth, proliferation and survival. Melanoma patients with BRAF mutations are usually treated with BRAF inhibitors such as vemurafenib, but responses are short-lived as drug resistant tumors metabolically switch to mitochondrial oxidative phosphorylation (OXPHOS) to escape metabolic stress-induced BRAF inhibition. Additionally, a large subset of melanoma utilizes OXPHOS in their metabolism, which can confer de novo resistance to BRAF inhibitors...
December 11, 2018: Oncotarget
Alice Indini, Carlo Alberto Tondini, Mario Mandalà
Approximately 50% of cutaneous melanomas harbor activating mutations of the BRAF-oncogene, making BRAF inhibitors (BRAFi) the standard treatment for this disease. However, disease responses are limited in duration mainly due to acquired resistance. Dual MAPK pathway inhibition with addition of a MEK inhibitor (MEKi) to a BRAFi improved the efficacy and tolerability compared with BRAFi alone. Cobimetinib (Cotellic® ) is an orally bioavailable, potent and selective MEKi, which significantly improved response rates when combined with BRAFi vemurafenib (median overall survival: 22...
January 14, 2019: Future Oncology
Sarah Erdmann, Diana Seidel, Heinz-Georg Jahnke, Marie Eichler, Jan-Christoph Simon, Andrea A Robitzki
The maximum response and 10-year survival rate for metastatic melanoma patients treated with standardised chemotherapy is still less than 15% and 10%, respectively. In contrast, oncogene targeting was found a promising tool for killing of BRAFV600 mutated melanoma cells. Nevertheless, despite improved response and survival rates, resistance acquisition remains an ongoing problem. In this context, the impact of chronic BRAF inhibition on the efficacy of commonly applied cytostatics is still unknown. In our study, human melanoma cells with BRAFV600E mutation were treated with chemotherapeutics and a BRAF inhibitor...
January 10, 2019: Scientific Reports
Gautham Gampa, Minjee Kim, Afroz S Mohammad, Karen E Parrish, Ann C Mladek, Jann N Sarkaria, William F Elmquist
Targeted inhibition of RAF and MEK by molecularly-targeted agents has been employed as a strategy to block aberrant MAPK signaling in melanoma. While the use of BRAF and MEK inhibitors, either as a single agent or in combination, improved efficacy in BRAF-mutant melanoma, initial responses are often followed by relapse due to acquired resistance. Also, BRAF inhibitors are associated with a paradoxical activation of MAPK pathway, causing the development of secondary malignancies. The use of panRAF inhibitors, i...
January 8, 2019: Journal of Pharmacology and Experimental Therapeutics
Anna Laurenzana, Margheri Francesca, Biagioni Alessio, Chillà Anastasia, Pimpinelli Nicola, Ruzzolini Jessica, Peppicelli Silvia, Andreucci Elena, Calorini Lido, Serratì Simona, Del Rosso Mario, Fibbi Gabriella
BACKGROUND: BRAF inhibitor (BRAF-I) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms behind BRAF-I responsiveness and acquired resistance is therefore an important issue. Here we assessed the role of urokinase type plasminogen activator receptor (uPAR) as a potentially valuable biomarker in the acquisition ofBRAF-I resistance in V600E mutant melanoma cells...
January 2, 2019: EBioMedicine
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