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    Exploiting Vulnerabilities in Cancers with Activated Extracellular Signal-Regulated Kinase (ERK1/2)

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    Author
    Martinez, Ramon
    0000-0002-0050-3172
    Advisor
    Shapiro, Paul, Ph.D.
    Date
    2021
    Embargo until
    08/04/2022
    Type
    dissertation
    
    Metadata
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    Abstract
    Constitutively active extracellular signal–regulated kinase (ERK) 1/2 signaling promotes cancer cell proliferation and survival. ERK1/2 pathway inhibitors are important therapies for treating many cancers, however, acquired resistance to most protein kinase inhibitors limit their ability to provide durable responses. Few studies have looked at the adaptive proteome responses of BRAF/MEK dual inhibitor resistant cells, and fewer still have established the utility of allosteric inhibitors targeting the ERK2 protein. The overall goal of the current study was to identify signaling mechanisms of therapeutic resistance and further investigate a previously identified inhibitor of melanoma cell growth with putative activity with the protein ERK2. To test this, we hypothesize that vulnerable targets can be identified for therapeutic intervention, and test if alternative inhibitors exhibit clinical potential for melanoma treatment in two specific aims. In Aim 1, we characterized the global protein changes happening in constitutively-activeERK1/2 melanoma cells models that developed resistance to BRAF (PLX4032) and MEK1/2 (AZD6244) inhibitors using mass spectrometry. We additionally identified putative targets for treatment and analyzed the potential for a metabolic inhibitor, niclosamide. In Aim 2, studies were focused on elucidating the structure-activity relationship and binding mechanism of a ERK2-specific inhibitor developed in house, SF-3-030. We identified chemical features required for biologic activity and global effects on gene and protein levels in A375 melanoma cells containing mutant BRAF(V600E). We then identified the mechanism of action of the inhibitor in preventing melanoma growth using mass spectrometry analysis. Overall, these studies help to elucidate how cells overcome currently used clinical therapies, what vulnerable markers can be identified and used for therapeutic intervention, and that inhibitors alternative to the clinical standard can show potential for melanoma treatment.
    Description
    University of Maryland, Baltimore. Pharmaceutical Sciences, Ph.D. 2021
    Keyword
    acquired resistance
    comparative proteomics
    covalent inhibitor
    melanoma cell growth
    Extracellular Signal-Regulated MAP Kinases
    Melanoma
    Oxidative Stress
    Spheroids, Cellular
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18124
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