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https://www.readbyqxmd.com/read/28203297/therapeutic-approach-to-treating-patients-with-braf-mutant-lung-cancer-latest-evidence-and-clinical-implications
#1
REVIEW
Adrianus J de Langen, Egbert F Smit
Lung adenocarcinoma is known for its high rate of somatic mutations and genomic rearrangements. The identification of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements that sensitize tumors to specific drugs has changed the therapeutic approach and prognosis in these molecularly-defined subgroups. Several other key genetic alterations have been identified, of which BRAF mutations are found in 4% of non-small cell lung cancer (NSCLC) cases. Targeted drugs against BRAF and downstream MEK were recently approved for the treatment of BRAF-positive melanoma and have entered clinical evaluation in NSCLC...
January 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28199980/pd-l1-up-regulation-in-melanoma-increases-disease-aggressiveness-and-is-mediated-through-mir-17-5p
#2
Valentina Audrito, Sara Serra, Aureliano Stingi, Francesca Orso, Federica Gaudino, Cinzia Bologna, Francesco Neri, Giulia Garaffo, Romina Nassini, Gianna Baroni, Eliana Rulli, Daniela Massi, Salvatore Oliviero, Roberto Piva, Daniela Taverna, Mario Mandalà, Silvia Deaglio
PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28198367/usp9x-regulates-ets-1-ubiquitination-and-stability-to-control-nras-expression-and-tumorigenicity-in-melanoma
#3
Harish Potu, Luke F Peterson, Malathi Kandarpa, Anupama Pal, Hanshi Sun, Alison Durham, Paul W Harms, Peter C Hollenhorst, Ugur Eskiocak, Moshe Talpaz, Nicholas J Donato
ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition...
February 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28197745/crosstalk-signaling-in-targeted-melanoma-therapy
#4
Svenja Meierjohann
Inhibition of the BRAF/MAPK pathway belongs to the standard therapies for patients with activating BRAF(V600E/K) mutations. However, even in well-responding tumors, anti-tumorigenic effect and clinical benefit are only transient, and the original tumors often relapse. This demonstrates that there are remaining residual tumors, which have withstood therapy-induced apoptosis and which have the potential to resume growth. Although BRAF mutant melanoma cells seem to depend on BRAF/MAPK signaling, the inhibition of this pathway triggers several events, which modulate the tumor as well as the tumor niche...
February 14, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28194436/real-time-genomic-profiling-of-histiocytoses-identifies-early-kinase-domain-braf-alterations-while-improving-treatment-outcomes
#5
Lynn H Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis X McCormack, Joseph Pressey, Michael S Grimley, Robert Lorsbach, Siraj Ali, Mark Bailey, Philip Stephens, Jeffrey S Ross, Vincent A Miller, Nicolas N Nassar, Ashish R Kumar
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28188776/aurora-a-overexpression-aurka-is-driven-by-foxm1-and-mapk-erk-activation-in-melanoma-cells-harbouring-braf-or-nras-mutations-impact-on-melanoma-prognosis-and-therapy
#6
Joan Anton Puig-Butille, Antònia Vinyals, Josep R Ferreres, Paula Aguilera, Eduard Cabré, Gemma Tell-Martí, Joaquim Marcoval, Francesca Mateo, Luís Palomero, Celia Badenas, Josep M Piulats, Josep Malvehy, Miquel A Pujana, Susana Puig, Àngels Fabra
The cell cycle-related genes AURORA A and Forkhead box M1 (FOXM1) are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF(V600E) mutation. AURKA overexpression may also be driven to increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK-ERK signalling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF(V600E) and ERK inhibition results in reduced AURKA transcription and expression...
February 7, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28181070/combining-forces-the-promise-and-peril-of-synergistic-immune-checkpoint-blockade-and-targeted-therapy-in-metastatic-melanoma
#7
David J Hermel, Patrick Ott
Both immune checkpoint inhibitors and molecularly targeted agents have dramatically improved clinical outcomes for patients with metastatic melanoma. These two therapeutic approaches harness distinct mechanistic pathways-on the one hand, monoclonal antibodies against the immune checkpoints CTLA-4 and PD-1/PD-L1 stimulate the T cell mediated host immune response, while targeted inhibitors of the proto-oncogenes BRAF and MEK disrupt constitutive kinase activity responsible for tumor growth. The prospect of combining these two treatment modalities has been proposed as a potential way to increase overall response rate, extend durability of the anti-tumor response, and circumvent the immune-mediated resistance to targeted therapy...
February 8, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28174173/the-apc-c-e3-ligase-complex-activator-fzr1-restricts-braf-oncogenic-function
#8
Lixin Wan, Ming Chen, Juxiang Cao, Xiangpeng Dai, Qing Yin, Jinfang Zhang, Su-Jung Song, Ying Lu, Jing Liu, Hiroyuki Inuzuka, Jesse M Katon, Kelsey Berry, Jacqueline Fung, Christopher Ng, Pengda Liu, Min Sup Song, Lian Xue, Roderick T Bronson, Marc W Kirschner, Rutao Cui, Pier Paolo Pandolfi, Wenyi Wei
BRAF drives tumorigenesis by coordinating the activation of RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathway(s) governing BRAF kinase activity and protein stability remains undefined. Here, we report that in primary cells with active APCFZR1, APCFZR1 earmarks BRAF for ubiquitination-mediated proteolysis, while in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APCFZR1, leading to elevation of a cohort of oncogenic APCFZR1 substrates to facilitate melanomagenesis...
February 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28169047/the-mitogen-activated-protein-kinase-pathway-in-melanoma-part-i-activation-and-primary-resistance-mechanisms-to-braf-inhibition
#9
REVIEW
Teresa Amaral, Tobias Sinnberg, Friedegund Meier, Clemens Krepler, Mitchell Levesque, Heike Niessner, Claus Garbe
Mitogen-activated protein kinase (MAPK) pathway has an important role in normal cells and can be activated under physiological conditions. MAPK pathway activation is a fundamental step in several intracellular processes requiring a sequential phosphorylation of the different pathway components. In normal cells, when MAPK pathway activation occurs, it leads to cell growth and differentiation. In order to prevent persistent MAPK pathway activation, physiological upstream negative feedback also takes place. In cells harbouring BRAFV600 mutations, the process leading to MAPK pathway activation is different, and the negative physiological feedback does not exist thus leading to permanent MAPK pathway activation, which ultimately can lead to uncontrolled proliferation...
February 3, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28162869/mapk-pathway-in-melanoma-part-ii-secondary-and-adaptive-resistance-mechanisms-to-braf-inhibition
#10
REVIEW
Teresa Amaral, Tobias Sinnberg, Friedegund Meier, Clemens Krepler, Mitchell Levesque, Heike Niessner, Claus Garbe
BRAF mutation can be identified in about 45% of the patients with metastatic melanoma. In these patients, BRAF and MEK inhibitors are able to induce rapid responses and to prolong survival. However, a significant percentage of patients will develop resistance to targeted therapy and will have progressive disease. MAPK pathway is the most important pathway involved in BRAF/MEK inhibition resistance, particularly MAPK pathway reactivation. Resistance mechanisms can be classified as 1) primary or intrinsic characterised by no response to therapy, 2) secondary or acquired with MAPK pathway reactivation after a time of tumour regression and 3) as adaptive with initial response and early resistance...
February 2, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28157711/the-repurposed-anthelmintic-mebendazole-in-combination-with-trametinib-suppresses-refractory-nrasq61k-melanoma
#11
Cynthia M Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Hong-Bin Fang, Maryam Abdussamad, Hengbo Zhou, John Zapas, Valerie Calvert, Emanuel F Petricoin, Michael B Atkins, Stephen W Byers, Dean S Rosenthal
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28152546/a-phase-1-dose-escalation-and-expansion-study-of-binimetinib-mek162-a-potent-and-selective-oral-mek1-2-inhibitor
#12
Johanna C Bendell, Milind Javle, Tanios S Bekaii-Saab, Richard S Finn, Zev A Wainberg, Daniel A Laheru, Colin D Weekes, Benjamin R Tan, Gazala N Khan, Mark M Zalupski, Jeffrey R Infante, Suzanne Jones, Kyriakos P Papadopoulos, Anthony W Tolcher, Renae E Chavira, Janna L Christy-Bittel, Emma Barrett, Amita Patnaik
BACKGROUND: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. METHODS: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design...
February 2, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28147313/mapk-pathway-inhibition-induces-met-and-gab1-levels-priming-braf-mutant-melanoma-for-rescue-by-hepatocyte-growth-factor
#13
Sean Caenepeel, Keegan Cooke, Sarah Wadsworth, Guo Huang, Lidia Robert, Blanca Homet Moreno, Giulia Parisi, Elaina Cajulis, Richard Kendall, Pedro Beltran, Antoni Ribas, Angela Coxon, Paul E Hughes
Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma...
January 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28145866/keap1-loss-modulates-sensitivity-to-kinase-targeted-therapy-in-lung-cancer
#14
Elsa B Krall, Belinda Wang, Diana M Munoz, Nina Ilic, Srivatsan Raghavan, Matthew J Niederst, Kristine Yu, David A Ruddy, Andrew J Aguirre, Jong Wook Kim, Amanda J Redig, Justin F Gainor, Juliet A Williams, John M Asara, John G Doench, Pasi A Janne, Alice T Shaw, Robert E McDonald Iii, Jeffrey A Engelman, Frank Stegmeier, Michael R Schlabach, William C Hahn
Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition...
February 1, 2017: ELife
https://www.readbyqxmd.com/read/28138035/co-targeting-hgf-cmet-signaling-with-mek-inhibitors-in-metastatic-uveal-melanoma
#15
Hanyin Cheng, Vivian Chua, Connie Liao, Timothy J Purwin, Mizue Terai, Ken Kageyama, Michael A Davies, Takami Sato, Andrew E Aplin
Metastatic uveal melanoma (UM) patients usually die within one year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in UM patients. Our previous work showed that HGF signaling elicits resistance to MEK inhibitors in metastatic UM. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and BMF, contributes to HGF-mediated resistance to MEK inhibitors...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28118616/micrornas-in-melanoma-development-and-resistance-to-target-therapy
#16
REVIEW
Luigi Fattore, Susan Costantini, Debora Malpicci, Ciro Francesco Ruggiero, Paolo Antonio Ascierto, Carlo M Croce, Rita Mancini, Gennaro Ciliberto
microRNAs constitute a complex class of pleiotropic post-transcriptional regulators of gene expression involved in the control of several physiologic and pathologic processes. Their mechanism of action is primarily based on the imperfect matching of a seed region located at the 5' end of a 21-23 nt sequence with a partially complementary sequence located in the 3' untranslated region of target mRNAs. This leads to inhibition of mRNA translation and eventually to its degradation. Individual miRNAs are capable of binding to several mRNAs and several miRNAs are capable of influencing the function of the same mRNAs...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28114255/novel-targeted-therapies-for-metastatic-melanoma
#17
Wade T Iams, Jeffrey A Sosman, Sunandana Chandra
Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms...
January 2017: Cancer Journal
https://www.readbyqxmd.com/read/28112278/cobimetinib-inhibiting-mek1-2-in-braf-v600-mutant-melanoma
#18
A Jimeno, J R Eagles
Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib...
November 2016: Drugs of Today
https://www.readbyqxmd.com/read/28108460/enhancer-remodeling-during-adaptive-bypass-to-mek-inhibition-is-attenuated-by-pharmacological-targeting-of-the-p-tefb-complex
#19
Jon S Zawistowski, Samantha M Bevill, Daniel R Goulet, Timothy J Stuhlmiller, Adriana S Beltran, Jose F Olivares-Quintero, Darshan Singh, Noah Sciaky, Joel S Parker, Naim U Rashid, Xin Chen, James S Duncan, Martin C Whittle, Steven P Angus, Sara Hanna Velarde, Brian T Golitz, Xiaping He, Charlene Santos, David B Darr, Kristalyn Gallagher, Lee M Graves, Charles M Perou, Lisa A Carey, H Shelton Earp, Gary L Johnson
Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment...
January 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28106277/tumor-targeting-salmonella-typhimurium-a1-r-sensitizes-melanoma-with-a-braf-v600e-mutation-to-vemurafenib-in-a-patient-derived-orthotopic-xenograft-pdox-nude-mouse-model
#20
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Ming Zhao, Yong Zhang, Bartosz Chmielowski, Tasuku Kiyuna, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Michiaki Unno, Fritz C Eilber, Robert M Hoffman
Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression...
January 20, 2017: Journal of Cellular Biochemistry
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