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Drug resistance in melanoma

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https://www.readbyqxmd.com/read/28634084/drug-delivery-to-melanoma-brain-metastases-can-current-challenges-lead-to-new-opportunities
#1
Gautham Gampa, Shruthi Vaidhyanathan, Jann N Sarkaria, William F Elmquist
Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease...
June 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28622068/salmonella-typhimurium-a1-r-targeting-of-a-chemotherapy-resistant-braf-v600e-melanoma-in-a-patient-derived-orthotopic-xenograft-pdox-model-is-enhanced-in-combination-with-either-vemurafenib-temozlomide
#2
Kei Kawaguchi, Kentaro Igarashi, Bartosz Chmielowski, Takashi Murakami, Tasuku Kiyuna, Ming Zhao, Yong Zhang, Scott D Nelson, Tara A Russell, Sarah M Dry, Arun S Singh, Yunfeng Li, Michiaki Unno, Fritz C Eilber, Robert M Hoffman
A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); treated with S...
June 16, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28615940/killing-malignant-melanoma-cells-with-protoporphyrin-ix-loaded-polymersome-mediated-photodynamic-therapy-and-cold-atmospheric-plasma
#3
Mian Wang, Benjamin M Geilich, Michael Keidar, Thomas J Webster
Traditional cancer treatments contain several limitations such as incomplete ablation and multidrug resistance. It is known that photodynamic therapy (PDT) is an effective treatment for several tumor types especially melanoma cells. During the PDT process, protoporphyrin IX (PpIX), an effective photosensitizer, can selectively kill cancer cells by activating a special light source. When tumor cells encapsulate a photosensitizer, they can be easily excited into an excited state by a light source. In this study, cold atmospheric plasma (CAP) was used as a novel light source...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28612614/-malignant-melanoma-from-classical-histology-towards-molecular-genetic-testing
#4
A Ryška, O Horký, J Berkovcová, I Tichá, M Kalinová, M Matějčková, Á Bóday, J Drábek, P Martínek, J Šimová, K Sieglová, H Vošmiková
BACKGROUND: Malignant melanoma is - in comparison with other skin tumors - a relatively rare malignant neoplasm with highly aggressive biologic behavior and variable prognosis. Recent data in pathology and molecular diagnostics indicate that malignant melanoma is in fact not a single entity but a group of different neoplasms with variable etiopathogenesis, biologic behavior and prognosis. New therapeutic options using targeted treatment blocking MAPK signaling pathway require testing of BRAF gene mutation status...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28607484/rare-cell-variability-and-drug-induced-reprogramming-as-a-mode-of-cancer-drug-resistance
#5
Sydney M Shaffer, Margaret C Dunagin, Stefan R Torborg, Eduardo A Torre, Benjamin Emert, Clemens Krepler, Marilda Beqiri, Katrin Sproesser, Patricia A Brafford, Min Xiao, Elliott Eggan, Ioannis N Anastopoulos, Cesar A Vargas-Garcia, Abhyudai Singh, Katherine L Nathanson, Meenhard Herlyn, Arjun Raj
Therapies that target signalling molecules that are mutated in cancers can often have substantial short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can result from secondary mutations, but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability. Here we show that human melanoma cells can display profound transcriptional variability at the single-cell level that predicts which cells will ultimately resist drug treatment...
June 15, 2017: Nature
https://www.readbyqxmd.com/read/28606996/targeting-endothelin-receptor-signalling-overcomes-heterogeneity-driven-therapy-failure
#6
Michael P Smith, Emily J Rowling, Zsofia Miskolczi, Jennifer Ferguson, Loredana Spoerri, Nikolas K Haass, Olivia Sloss, Sophie McEntegart, Imanol Arozarena, Alex von Kriegsheim, Javier Rodriguez, Holly Brunton, Jivko Kmarashev, Mitchell P Levesque, Reinhard Dummer, Dennie T Frederick, Miles C Andrews, Zachary A Cooper, Keith T Flaherty, Jennifer A Wargo, Claudia Wellbrock
Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a "MITF-high" phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance "AXL-high" phenotype. > 50% of melanomas progress with enriched "AXL-high" populations, and because AXL is linked to de-differentiation and invasiveness avoiding an "AXL-high relapse" is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF-induced expression of endothelin 1 (EDN1)...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28599981/p90rsk-blockade-inhibits-dual-braf-and-mek-inhibitor-resistant-melanoma-by-targeting-protein-synthesis
#7
Nicholas Theodosakis, Goran Micevic, Casey G Langdon, Alessandra Ventura, Robert Means, David F Stern, Marcus W Bosenberg
Despite improvements in survival in metastatic melanoma with combined BRAF and MEK inhibitor treatment, the overwhelming majority of patients eventually acquire resistance to both agents. Consequently, new targets for therapy in resistant tumors are currently being evaluated. Previous studies have identified p90RSK family kinases as key factors for growth and proliferation, as well as protein synthesis via assembly of the m(7)-GTP cap-dependent translation complex. We sought to evaluate inhibitors of p90RSK family members: BI-D1870 and BRD7389, for their ability to inhibit both proliferation and protein synthesis in patient-derived melanoma cell lines with acquired resistance to combined treatment with the BRAF inhibitor vemurafenib and MEK inhibitor selumetinib...
June 6, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28599271/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#8
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28597996/sensitization-of-melanoma-cells-to-temozolomide-by-overexpression-of-microrna-203-through-direct-targeting-of-glutaminase-mediated-glutamine-metabolism
#9
X Chang, W Zhu, H Zhang, S Lian
BACKGROUND: Malignant melanoma (MM) is an aggressive malignancy, which accounts for 80% of skin cancer-related deaths and is notably resistant to conventional chemotherapeutic agents. One of the most common treatments for melanoma is surgery, followed by various combinations of chemotherapy drugs. AIM: To investigate the role of microRNA (miR)-203 in sensitivity of MM cells to the chemotherapy drug temozolomide (TMZ). METHODS: Using quantitative reverse transcription PCR, we measured the expression of miR-203 in an MM cell line...
June 9, 2017: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/28595656/ros-production-induced-by-braf-inhibitor-treatment-rewires-metabolic-processes-affecting-cell-growth-of-melanoma-cells
#10
Giulia Cesi, Geoffroy Walbrecq, Andreas Zimmer, Stephanie Kreis, Claude Haan
BACKGROUND: Most melanoma patients with BRAF(V600E) positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAF(V600E) has been shown to affect the metabolism...
June 8, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28591687/mtor-mediated-na-ca-2-exchange-affects-cell-proliferation-and-metastasis-of-melanoma-cells
#11
Yi Yang, Zhanpeng Luo, Yonghong Hao, Wei Ba, Rui Wang, Wenjuan Wang, Xiangyu Ding, Chengxin Li
Melanoma is a common malignant tumor, which is associated with high mortality rate. The multiple-drug resistance of tumor cells often results in failure of chemotherapy. The aim of our study is to investigate the expression of Nav 1.6 in human melanoma cells and human epidermal melanocytes. Additionally, the effect of Na+channels on Ca+ current and mTOR activity in melanoma cells were also analyzed. The protein expression levels of Nav1.6 in human melanocyte PIG1, WM266 and WM115 cells were investigated by western blot...
June 4, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28585612/-recent-advances-of-immunooncology-in-the-treatment-of-solid-tumours-and-haematological-malignancies-the-immune-checkpoint-inhibitors
#12
Viktória Fésüs
Cancer immunotherapy is coming of age, as outstanding results can be achieved in the therapy of cancer with poor prognosis by altering the patients' immune system and by promoting the immune response against tumours. Amongst immunotherapies, the immune checkpoint inhibitors (ICI) proved to be the most effective, primarily in the treatment of solid tumours, including melanoma, non-small cell lung carcinoma, and classical Hodgkin's lymphoma. The reason for this efficacy is the immunosuppressive microenvironment typical for many cancer types, directly and indirectly inhibiting effector T-cell responses...
June 6, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28585089/combination-of-cationic-dexamethasone-derivative-and-stat3-inhibitor-wp1066-for-aggressive-melanoma-a-strategy-for-repurposing-a-phase-i-clinical-trial-drug
#13
Samaresh Sau, Sujan Kumar Mondal, Sushil K Kashaw, Arun K Iyer, Rajkumar Banerjee
Glucocorticoid, such as dexamethasone (Dex) is often used along with chemotherapy to antagonize side effects of chemotherapy. However, sustained use of Dex frequently develops drug resistance in patients. As a strategy to re-induce drug sensitivity, we planned to modify Dex by chemically conjugating it with twin ten carbon aliphatic chain containing cationic lipid. The resultant molecule, DX10, inhibited STAT3 activation through lowering the production of IL-6. To enhance the STAT3 inhibitory effect of DX10, we used WP (a commercially available STAT3 inhibitor) along with DX10...
June 5, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28579578/the-t-box-transcription-factor-3-in-development-and-cancer
#14
Tarryn Willmer, Aretha Cooper, Jade Peres, Rehana Omar, Sharon Prince
T-box factors comprise an archaic family of evolutionary conserved transcription factors that regulate patterns of gene expression essential for embryonic development. The T-box transcription factor 3 (TBX3), a member of this family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes...
June 4, 2017: Bioscience Trends
https://www.readbyqxmd.com/read/28576947/the-slow-cycling-phenotype-a-growing-problem-for-treatment-resistance-in-melanoma
#15
REVIEW
Antonio Ahn, Aniruddha Chatterjee, Michael R Eccles
Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance...
June 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28574827/induction-of-immunoglobulin-transcription-factor-2-and-resistance-to-mek-inhibitor-in-melanoma-cells
#16
Eun-Hye Hur, Bon-Kwan Goo, Juhyun Moon, Yunsuk Choi, Jung Jin Hwang, Choung-Soo Kim, Kyun Seop Bae, Jene Choi, Suk Young Cho, Sang-Hwa Yang, Jeongbeob Seo, Gilnam Lee, Je-Hwan Lee
Primary or acquired resistance to MEK inhibitors has been a barrier to successful treatment with MEK inhibitors in many tumors. In this study, we analyzed genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines to identify candidate genes whose expression changes are associated with responses to a MEK inhibitor, selumetinib (AZD6244). Of 62 identified differentially expressed genes, we selected Immunoglobulin Transcription Factor 2, also known as transcription factor 4 as a potential drug resistance marker for further analysis...
May 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28574815/prpf-overexpression-induces-drug-resistance-through-actin-cytoskeleton-rearrangement-and-epithelial-mesenchymal-transition
#17
Salman Ul Islam, Adeeb Shehzad, Jong Kyung Sonn, Young Sup Lee
Pre-mRNA processing factor (PRPF) 4B kinase belongs to the CDK-like kinase family, and is involved in pre-mRNA splicing, and in signal transduction. In this study, we observed that PRPF overexpression decreased the intracellular levels of reactive oxygen species, and inhibited resveratrol-induced apoptosis by activating the cell survival signaling proteins NFκB, ERK, and c-MYC in HCT116 human colon cancer cells. PRPF overexpression altered cellular morphology, and rearranged the actin cytoskeleton, by regulating the activity of Rho family proteins...
May 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28560396/mitochondrial-ca2-removal-amplifies-trail-cytotoxicity-toward-apoptosis-resistant-tumor-cells-via-promotion-of-multiple-cell-death-modalities
#18
Natsuhiko Takata, Yohei Ohshima, Miki Suzuki-Karasaki, Yukihiro Yoshida, Yasuaki Tokuhashi, Yoshihiro Suzuki-Karasaki
Ca2+ has emerged as a new target for cancer treatment since tumor-specific traits in Ca2+ dynamics contributes to tumorigenesis, malignant phenotypes, drug resistance, and survival in different tumor types. However, Ca2+ has a dual (pro-death and pro-survival) function in tumor cells depending on the experimental conditions. Therefore, it is necessary to minimize the onset of the pro-survival Ca2+ signals caused by the therapy. For this purpose, a better understanding of pro-survival Ca2+ pathways in cancer cells is critical...
May 25, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28551321/microrna-driven-deregulation-of-cytokine-expression-helps-development-of-drug-resistance-in-metastatic-melanoma
#19
Luigi Fattore, Andrea Sacconi, Rita Mancini, Gennaro Ciliberto
microRNAs are major components of the eukaryotic post-transcriptional machinery and are frequently deregulated during cancer development. Increasing evidence points to them also as key players in the establishment of drug resistance. In this review, we provide an updated overview of the role of miRNAs in melanoma development and drug resistance and postulate that they are able to drive these processes in concert with deregulation of inflammatory and angiogenic cytokine expression. Notably, we have identified by querying the Cancer Genome Atlas database, a defined set of miRNAs which mostly have an impact on the development of melanoma and have recognized the main downstream pathways controlled by them...
May 17, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28548101/corrigendum-targeting-bmk1-impairs-the-drug-resistance-to-combined-inhibition-of-braf-and-mek1-2-in-melanoma
#20
Chengli Song, Lina Wang, Qiang Xu, Kai Wang, Dan Xie, Zhe Yu, Kui Jiang, Lujian Liao, John R Yates, Jiing-Dwan Lee, Qingkai Yang
This corrects the article DOI: 10.1038/srep46244.
May 26, 2017: Scientific Reports
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