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  1. Article ; Online: The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling.

    Brijal M Desai / Jessie Villanueva / Thierry-Thien K Nguyen / Mercedes Lioni / Min Xiao / Jun Kong / Clemens Krepler / Adina Vultur / Keith T Flaherty / Katherine L Nathanson / Keiran S M Smalley / Meenhard Herlyn

    PLoS ONE, Vol 8, Iss 3, p e

    2013  Volume 59588

    Abstract: Although cyclin dependent kinase (CDK)-2 is known to be dispensable for the growth of most tumors, it is thought to be important for the proliferation of melanoma cells, where its expression is controlled by the melanocyte-lineage specific transcription ... ...

    Abstract Although cyclin dependent kinase (CDK)-2 is known to be dispensable for the growth of most tumors, it is thought to be important for the proliferation of melanoma cells, where its expression is controlled by the melanocyte-lineage specific transcription factor MITF. Treatment of a panel of melanoma cells with the CDK inhibitor dinaciclib led to a concentration-dependent inhibition of growth under both 2D adherent and 3D organotypic cell culture conditions. Dinaciclib targeted melanoma cell lines regardless of cdk2 or MITF levels. Inhibition of growth was associated with a rapid induction of G2/M cell arrest and apoptosis. Treatment of human melanoma mouse xenografts with dinaciclib led to tumor regression associated with reduced retinoblastoma protein phosphorylation and Bcl-2 expression. Further mechanistic studies revealed that dinaciclib induces p53 expression whilst simultaneously downregulating the expression of the anti-apoptotic factors Mcl-1 and XIAP. To clarify the role of p53 activation in the dinaciclib-induced cell death, we generated melanoma cell lines in which p53 expression was knocked down using a shRNA lentiviral vector. Knockdown of p53 completely abolished the induction of apoptosis seen following dinaciclib treatment as shown by a lack of annexin-V staining and caspase-3 cleavage. Altogether, these data show that dinaciclib induces apoptosis in a large panel of melanoma cell lines through a mechanism requiring p53 expression.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Functional profiling of live melanoma samples using a novel automated platform.

    Adam Schayowitz / Greg Bertenshaw / Emiko Jeffries / Timothy Schatz / James Cotton / Jessie Villanueva / Meenhard Herlyn / Clemens Krepler / Adina Vultur / Wei Xu / Gordon H Yu / Lynn Schuchter / Douglas P Clark

    PLoS ONE, Vol 7, Iss 12, p e

    2012  Volume 52760

    Abstract: This proof-of-concept study was designed to determine if functional, pharmacodynamic profiles relevant to targeted therapy could be derived from live human melanoma samples using a novel automated platform.A series of 13 melanoma cell lines was briefly ... ...

    Abstract This proof-of-concept study was designed to determine if functional, pharmacodynamic profiles relevant to targeted therapy could be derived from live human melanoma samples using a novel automated platform.A series of 13 melanoma cell lines was briefly exposed to a BRAF inhibitor (PLX-4720) on a platform employing automated fluidics for sample processing. Levels of the phosphoprotein p-ERK in the mitogen-activated protein kinase (MAPK) pathway from treated and untreated sample aliquots were determined using a bead-based immunoassay. Comparison of these levels provided a determination of the pharmacodynamic effect of the drug on the MAPK pathway. A similar ex vivo analysis was performed on fine needle aspiration (FNA) biopsy samples from four murine xenograft models of metastatic melanoma, as well as 12 FNA samples from patients with metastatic melanoma.Melanoma cell lines with known sensitivity to BRAF inhibitors displayed marked suppression of the MAPK pathway in this system, while most BRAF inhibitor-resistant cell lines showed intact MAPK pathway activity despite exposure to a BRAF inhibitor (PLX-4720). FNA samples from melanoma xenografts showed comparable ex vivo MAPK activity as their respective cell lines in this system. FNA samples from patients with metastatic melanoma successfully yielded three categories of functional profiles including: MAPK pathway suppression; MAPK pathway reactivation; MAPK pathway stimulation. These profiles correlated with the anticipated MAPK activity, based on the known BRAF mutation status, as well as observed clinical responses to BRAF inhibitor therapy.Pharmacodynamic information regarding the ex vivo effect of BRAF inhibitors on the MAPK pathway in live human melanoma samples can be reproducibly determined using a novel automated platform. Such information may be useful in preclinical and clinical drug development, as well as predicting response to targeted therapy in individual patients.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

    Ileabett M Echevarría‐Vargas / Patricia I Reyes‐Uribe / Adam N Guterres / Xiangfan Yin / Andrew V Kossenkov / Qin Liu / Gao Zhang / Clemens Krepler / Chaoran Cheng / Zhi Wei / Rajasekharan Somasundaram / Giorgos Karakousis / Wei Xu / Jennifer JD Morrissette / Yiling Lu / Gordon B Mills / Ryan J Sullivan / Miao Benchun / Dennie T Frederick /
    Genevieve Boland / Keith T Flaherty / Ashani T Weeraratna / Meenhard Herlyn / Ravi Amaravadi / Lynn M Schuchter / Christin E Burd / Andrew E Aplin / Xiaowei Xu / Jessie Villanueva

    EMBO Molecular Medicine, Vol 10, Iss 5, Pp n/a-n/a (2018)

    2018  

    Abstract: Abstract Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug ...

    Abstract Abstract Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS‐mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS‐mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS‐mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co‐targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment‐resistant tumor types.
    Keywords BET ; combination therapy ; drug resistance ; melanoma ; mutant NRAS ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 570
    Language English
    Publishing date 2018-05-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma

    Jessie Villanueva / Jeffrey R. Infante / Clemens Krepler / Patricia Reyes-Uribe / Minu Samanta / Hsin-Yi Chen / Bin Li / Rolf K. Swoboda / Melissa Wilson / Adina Vultur / Mizuho Fukunaba-Kalabis / Bradley Wubbenhorst / Thomas Y. Chen / Qin Liu / Katrin Sproesser / Douglas J. DeMarini / Tona M. Gilmer / Anne-Marie Martin / Ronen Marmorstein /
    David C. Schultz / David W. Speicher / Giorgos C. Karakousis / Wei Xu / Ravi K. Amaravadi / Xiaowei Xu / Lynn M. Schuchter / Meenhard Herlyn / Katherine L. Nathanson

    Cell Reports, Vol 4, Iss 6, Pp 1090-

    2013  Volume 1099

    Abstract: Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not ... ...

    Abstract Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2013-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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