{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/5733"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/5733","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma","abstract":"Genomic 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).","abstract_html":"Genomic 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).","abstract_has_math":false,"creators":["Eskiocak, Banu"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["DeBerardinis, Ralph J.","White, Michael A.","Brekken, Rolf A.","Cobb, Melanie H."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-08-24T20:38:12Z","date_published":"2018-08-24T20:38:12Z","updated_at":"2026-07-24T05:52:15Z","subjects":["Biomarkers","DNA Copy Number Variations","MAP Kinase Signaling System","Melanoma","Skin Neoplasms"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1049807458"],"render_values":[{"text":"1049807458","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/5733","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["DeBerardinis, Ralph J.","White, Michael A.","Brekken, Rolf A.","Cobb, Melanie H."]},{"key":"dc:creator","label":"Author","values":["Eskiocak, Banu"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-08-24T20:38:12Z","2016-08","2016-06-23","August 2016","2018-08-24T20:31:42Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biomarkers","DNA Copy Number Variations","MAP Kinase Signaling System","Melanoma","Skin Neoplasms"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/5733","1049807458"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Genomic 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)."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma"]}]}],"canonical_facts":{"dc:contributor":["DeBerardinis, Ralph J.","White, Michael A.","Brekken, Rolf A.","Cobb, Melanie H."],"dc:creator":["Eskiocak, Banu"],"dc:date":["2018-08-24T20:38:12Z","2016-08","2016-06-23","August 2016","2018-08-24T20:31:42Z"],"dc:description":["Genomic 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)."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/5733","1049807458"],"dc:language":["en"],"dc:subject":["Biomarkers","DNA Copy Number Variations","MAP Kinase Signaling System","Melanoma","Skin Neoplasms"],"dc:title":["Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:15Z"}