Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

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dc.contributor.advisorDeBerardinis, Ralph J.en
dc.contributor.committeeMemberWhite, Michael A.en
dc.contributor.committeeMemberBrekken, Rolf A.en
dc.contributor.committeeMemberCobb, Melanie H.en
dc.creatorEskiocak, Banuen
dc.date.accessioned2018-08-24T20:38:12Z
dc.date.available2018-08-24T20:38:12Z
dc.date.created2016-08
dc.date.issued2016-06-23
dc.date.submittedAugust 2016
dc.date.updated2018-08-24T20:31:42Z
dc.description.abstractGenomic diversity and adaptive plasticity of melanoma tumors limit durable control with conventional and targeted therapies. Nevertheless, pathological activation of the ERK1/2 regulatory system is a linchpin tumorigenic mechanism associated with the majority of both primary and recurrent disease. To avoid common resistance mechanisms associated with perdurance of ERK1/2 signaling, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling. Such targets could be leveraged in jiu jitsu fashion to breach selective pressure to engage any of the many BRAF-independent ERK1/2 pathway activation mechanisms. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-feature genetic biomarker. This biomarker, or the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors (detectable in 25% of melanoma patients) and identify a cohort of TBK1/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy (detectable in 9.9% of melanomas).en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1049807458
dc.identifier.urihttps://hdl.handle.net/2152.5/5733
dc.language.isoenen
dc.subjectBiomarkersen
dc.subjectDNA Copy Number Variationsen
dc.subjectMAP Kinase Signaling Systemen
dc.subjectMelanomaen
dc.subjectSkin Neoplasmsen
dc.titleBiomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanomaen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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