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Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations.
Lehmann BD, Shaver TM, Johnson DB, Li Z, Gonzalez-Ericsson PI, Sánchez V, Shyr Y, Sanders ME, Pietenpol JA
(2019) Mol Cancer Res 17: 1842-1853
MeSH Terms: Algorithms, Cell Line, Tumor, Databases, Genetic, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Kinase Kinases, Male, Melanoma, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Sequence Analysis, RNA, Sequence Deletion, Survival Analysis, Translocation, Genetic, Up-Regulation
Show Abstract · Added March 30, 2020
Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (, and ). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. IMPLICATIONS: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
©2019 American Association for Cancer Research.
0 Communities
1 Members
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17 MeSH Terms
Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types.
Greenplate AR, McClanahan DD, Oberholtzer BK, Doxie DB, Roe CE, Diggins KE, Leelatian N, Rasmussen ML, Kelley MC, Gama V, Siska PJ, Rathmell JC, Ferrell PB, Johnson DB, Irish JM
(2019) Cancer Immunol Res 7: 86-99
MeSH Terms: Adenoids, Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Female, Humans, Imidazoles, MAP Kinase Kinase Kinases, Male, Middle Aged, Monitoring, Immunologic, Neoplasms, Oximes, Palatine Tonsil, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, T-Lymphocytes
Show Abstract · Added November 11, 2018
Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types.
©2018 American Association for Cancer Research.
3 Communities
1 Members
0 Resources
19 MeSH Terms
Assembly Dynamics and Stoichiometry of the Apoptosis Signal-regulating Kinase (ASK) Signalosome in Response to Electrophile Stress.
Federspiel JD, Codreanu SG, Palubinsky AM, Winland AJ, Betanzos CM, McLaughlin B, Liebler DC
(2016) Mol Cell Proteomics 15: 1947-61
MeSH Terms: 14-3-3 Proteins, Aldehydes, Epitopes, HEK293 Cells, Humans, Isotope Labeling, MAP Kinase Kinase Kinase 5, MAP Kinase Kinase Kinases, Mass Spectrometry, Protein Interaction Maps, Proteomics, Signal Transduction
Show Abstract · Added April 25, 2016
Apoptosis signal-regulating kinase 1 (ASK1) is a key sensor kinase in the mitogen-activated protein kinase pathway that transduces cellular responses to oxidants and electrophiles. ASK1 is regulated by a large, dynamic multiprotein signalosome complex, potentially including over 90 reported ASK1-interacting proteins. We employed both shotgun and targeted mass spectrometry assays to catalogue the ASK1 protein-protein interactions in HEK-293 cells treated with the prototypical lipid electrophile 4-hydroxy-2-nonenal (HNE). Using both epitope-tagged overexpression and endogenous expression cell systems, we verified most of the previously reported ASK1 protein-protein interactions and identified 14 proteins that exhibited dynamic shifts in association with ASK1 in response to HNE stress. We used precise stable isotope dilution assays to quantify protein stoichiometry in the ASK signalosome complex and identified ASK2 at a 1:1 stoichiometric ratio with ASK1 and 14-3-3 proteins (YWHAQ, YWHAB, YWHAH, and YWHAE) collectively at a 0.5:1 ratio with ASK1 as the main components. Several other proteins, including ASK3, PARK7, PRDX1, and USP9X were detected with stoichiometries of 0.1:1 or less. These data support an ASK signalosome comprising a multimeric core complex of ASK1, ASK2, and 14-3-3 proteins, which dynamically engages other binding partners needed to mediate diverse stress-response signaling events. This study further demonstrates the value of combining global and targeted MS approaches to interrogate multiprotein complex composition and dynamics.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
0 Resources
12 MeSH Terms
Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling.
Pawlikowski JS, Brock C, Chen SC, Al-Olabi L, Nixon C, McGregor F, Paine S, Chanudet E, Lambie W, Holmes WM, Mullin JM, Richmond A, Wu H, Blyth K, King A, Kinsler VA, Adams PD
(2015) J Invest Dermatol 135: 2093-2101
MeSH Terms: Animals, Child, DNA, Disease Models, Animal, Female, Humans, MAP Kinase Kinase Kinases, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Monomeric GTP-Binding Proteins, Mutation, Nevus, Pigmented, Sequence Analysis, DNA, Signal Transduction, Skin Neoplasms, Wnt Proteins
Show Abstract · Added May 19, 2015
Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.
2 Communities
2 Members
0 Resources
18 MeSH Terms
Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice.
de la Croix Ndong J, Stevens DM, Vignaux G, Uppuganti S, Perrien DS, Yang X, Nyman JS, Harth E, Elefteriou F
(2015) J Bone Miner Res 30: 55-63
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Bone Regeneration, Cell Differentiation, Disease Models, Animal, Drug Delivery Systems, Humans, MAP Kinase Kinase Kinases, Mesenchymal Stem Cells, Mice, Mice, Knockout, Nanoparticles, Neurofibromatosis 1, Neurofibromin 1, Protein Kinase Inhibitors, Pseudarthrosis, Pyridones, Pyrimidinones
Show Abstract · Added July 28, 2014
Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase-activating protein neurofibromin. Non-bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFβ. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1(flox/flox) bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx (-/-) mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis.
© 2014 American Society for Bone and Mineral Research.
2 Communities
7 Members
0 Resources
18 MeSH Terms
Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer.
Giltnane JM, Balko JM
(2014) Discov Med 17: 275-83
MeSH Terms: Animals, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mice, Mutation, Neoplasm Recurrence, Local, Treatment Outcome, Triple Negative Breast Neoplasms, ras Proteins
Show Abstract · Added January 20, 2015
"Triple negative" breast cancer (TNBC) is the most aggressive and least common clinical subtype of breast cancer. As its nomenclature implies, TNBC lacks specific biomarker expression marking response to an effective targeted therapy. The incidence of TNBC is higher in young minority women who suffer from high rates of early recurrence and death from their disease. Mounting preclinical evidence supports targeting the Ras/MAPK cell signaling pathway in the TNBC subtype, despite large genomic surveys such as The Cancer Genome Atlas demonstrating infrequent canonical mutations in this pathway. Due to the early spread of TNBC, targeted treatment in the neoadjuvant setting may offer the effective therapeutic punch needed to eliminate micro-metastatic disease and reduce mortality. Herein, we will review the evidence supporting clinical trials of targeted inhibitors of the Ras/MAPK pathway in TNBC, and discuss the obstacles and opportunities of this approach.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1-induced inflammatory responses to corneal injury.
Yang Y, Yang H, Wang Z, Varadaraj K, Kumari SS, Mergler S, Okada Y, Saika S, Kingsley PJ, Marnett LJ, Reinach PS
(2013) Cell Signal 25: 501-11
MeSH Terms: Animals, Arachidonic Acids, Benzoxazines, Calcium, Calcium Channel Blockers, Cell Line, Disease Models, Animal, Endocannabinoids, Epithelial Cells, Epithelium, Corneal, Glycerides, Humans, Immunity, Innate, MAP Kinase Kinase Kinases, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Morpholines, Naphthalenes, Patch-Clamp Techniques, Pertussis Toxin, Protein Binding, RNA Interference, RNA, Small Interfering, Receptor, Cannabinoid, CB1, Signal Transduction, TRPV Cation Channels, Wound Healing
Show Abstract · Added June 1, 2014
Cannabinoid receptor type 1 (CB1)-induced suppression of transient receptor potential vanilloid type 1 (TRPV1) activation provides a therapeutic option to reduce inflammation and pain in different animal disease models through mechanisms involving dampening of TRPV1 activation and signaling events. As we found in both mouse corneal epithelium and human corneal epithelial cells (HCEC) that there is CB1 and TRPV1 expression colocalization based on overlap of coimmunostaining, we determined in mouse corneal wound healing models and in human corneal epithelial cells (HCEC) if they interact with one another to reduce TRPV1-induced inflammatory and scarring responses. Corneal epithelial debridement elicited in vivo a more rapid wound healing response in wildtype (WT) than in CB1(-/-) mice suggesting functional interaction between CB1 and TRPV1. CB1 activation by injury is tenable based on the identification in mouse corneas of 2-arachidonylglycerol (2-AG) with tandem LC-MS/MS, a selective endocannabinoid CB1 ligand. Suppression of corneal TRPV1 activation by CB1 is indicated since following alkali burning, CB1 activation with WIN55,212-2 (WIN) reduced immune cell stromal infiltration and scarring. Western blot analysis of coimmunoprecipitates identified protein-protein interaction between CB1 and TRPV1. Other immunocomplexes were also identified containing transforming growth factor kinase 1 (TAK1), TRPV1 and CB1. CB1 siRNA gene silencing prevented suppression by WIN of TRPV1-induced TAK1-JNK1 signaling. WIN reduced TRPV1-induced Ca(2+) transients in fura2-loaded HCEC whereas pertussis toxin (PTX) preincubation obviated suppression by WIN of such rises caused by capsaicin (CAP). Whole cell patch clamp analysis of HCEC showed that WIN blocked subsequent CAP-induced increases in nonselective outward currents. Taken together, CB1 activation by injury-induced release of endocannabinoids such as 2-AG downregulates TRPV1 mediated inflammation and corneal opacification. Such suppression occurs through protein-protein interaction between TRPV1 and CB1 leading to declines in TRPV1 phosphorylation status. CB1 activation of the GTP binding protein, G(i/o) contributes to CB1 mediated TRPV1 dephosphorylation leading to TRPV1 desensitization, declines in TRPV1-induced increases in currents and pro-inflammatory signaling events.
Copyright © 2012 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
28 MeSH Terms
BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.
Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones CL, Sosman JA, Ribas A, Zhao Z, Pao W
(2012) Cancer Discov 2: 791-7
MeSH Terms: Aged, Cell Line, Tumor, Genome, Human, Humans, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Male, Melanoma, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones
Show Abstract · Added September 3, 2013
UNLABELLED - Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma.
SIGNIFICANCE - This study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAF(L597R)-mutant melanoma.
0 Communities
6 Members
0 Resources
13 MeSH Terms
Immunology: TRIM5 does double duty.
Aiken C, Joyce S
(2011) Nature 472: 305-6
MeSH Terms: Animals, Capsid, Carrier Proteins, HIV-1, Humans, Immunity, Innate, MAP Kinase Kinase Kinases, NF-kappa B, Receptors, Pattern Recognition, Retroviridae, Transcription Factor AP-1, Ubiquitin, Ubiquitin-Protein Ligases
Added January 20, 2015
0 Communities
2 Members
0 Resources
13 MeSH Terms
Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination.
Lamb A, Yang XD, Tsang YH, Li JD, Higashi H, Hatakeyama M, Peek RM, Blanke SR, Chen LF
(2009) EMBO Rep 10: 1242-9
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Cytokines, Gene Expression Regulation, Humans, Inflammation, Lysine, MAP Kinase Kinase Kinases, Mice, NF-kappa B, TNF Receptor-Associated Factor 6, Ubiquitin
Show Abstract · Added March 5, 2014
Helicobacter pylori-initiated chronic gastritis is characterized by the cag pathogenicity island-dependent upregulation of proinflammatory cytokines, which is largely mediated by the transcription factor nuclear factor (NF)-kappaB. However, the cag pathogenicity island-encoded proteins and cellular signalling molecules that are involved in H. pylori-induced NF-kappaB activation and inflammatory response remain unclear. Here, we show that H. pylori virulence factor CagA and host protein transforming growth factor-beta-activated kinase 1 (TAK1) are essential for H. pylori-induced activation of NF-kappaB. CagA physically associates with TAK1 and enhances its activity and TAK1-induced NF-kappaB activation through the tumour necrosis factor receptor-associated factor 6-mediated, Lys 63-linked ubiquitination of TAK1. These findings show that polyubiquitination of TAK1 regulates the activation of NF-kappaB, which in turn is used by H. pylori CagA for the H. pylori-induced inflammatory response.
0 Communities
1 Members
0 Resources
14 MeSH Terms