Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors can result in enhanced EGFR signaling, uncontrolled proliferation, and may provide a mechanism for chemotherapy resistance. UBE4B, an E3/E4 ubiquitin ligase, ubiquitinates the EGFR and promotes its lysosomal degradation ultimately attenuating EGFR signaling. Interestingly, the UBE4B gene lies in a chromosomal region (1p36) whose loss is correlated with poor patient outcomes due to inefficient EGFR degradation and enhanced cell proliferation. We examined whether depletion of UBE4B in a chemoresistant neuroblastoma cell line would affect tumor responses to drugs that specifically target selected proteins that are upregulated in the absence of UBE4B. UBE4B depletion in a resistant neuroblastoma cell line resulted in a number of proteins whose levels were altered, including an increase in EGFR and STAT5a levels. We observed that treatment with Cetuximab, a therapeutic antibody targeting the EGFR, significantly inhibited the proliferation of neuroblastoma cells depleted of UBE4B. Addition of a STAT5 inhibitor potentiated the Cetuximab-induced inhibition of proliferation, reduced migration, and enhanced apoptosis in UBE4B-depleted neuroblastoma cells more than either drug treatment alone. Thus, screening resected patient tumors for 1p36 status and UBE4B levels may enable a novel treatment strategy in which selected patients who have low UBE4B-expressing tumors may benefit from simultaneously targeting multiple EGFR signaling pathways.
","abstract_html":"<p>Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors can result in enhanced EGFR signaling, uncontrolled proliferation, and may provide a mechanism for chemotherapy resistance. UBE4B, an E3/E4 ubiquitin ligase, ubiquitinates the EGFR and promotes its lysosomal degradation ultimately attenuating EGFR signaling. Interestingly, the UBE4B gene lies in a chromosomal region (1p36) whose loss is correlated with poor patient outcomes due to inefficient EGFR degradation and enhanced cell proliferation. We examined whether depletion of UBE4B in a chemoresistant neuroblastoma cell line would affect tumor responses to drugs that specifically target selected proteins that are upregulated in the absence of UBE4B. UBE4B depletion in a resistant neuroblastoma cell line resulted in a number of proteins whose levels were altered, including an increase in EGFR and STAT5a levels. We observed that treatment with Cetuximab, a therapeutic antibody targeting the EGFR, significantly inhibited the proliferation of neuroblastoma cells depleted of UBE4B. Addition of a STAT5 inhibitor potentiated the Cetuximab-induced inhibition of proliferation, reduced migration, and enhanced apoptosis in UBE4B-depleted neuroblastoma cells more than either drug treatment alone. Thus, screening resected patient tumors for 1p36 status and UBE4B levels may enable a novel treatment strategy in which selected patients who have low UBE4B-expressing tumors may benefit from simultaneously targeting multiple EGFR signaling pathways.</p>","abstract_has_math":false,"creators":["Savage, David James","https://orcid.org/0000-0003-4690-5115
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Andrew J. Bean, Ph.D.","Edgar T. Walters, Ph.D.","Shane R. Cunha, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-08-01T07:00:00Z","date_published":"2018-08-01T07:00:00Z","updated_at":"2026-07-24T05:49:30Z","subjects":["Neuroblastoma","UBE4B","Cetuximab","STAT5","EGFR","Cancer Biology","Medicine and Health Sciences","Other Neuroscience and Neurobiology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/872","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Andrew J. Bean, Ph.D.","Edgar T. Walters, Ph.D.","Shane R. Cunha, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Savage, David James","https://orcid.org/0000-0003-4690-5115
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"]},{"key":"dc:title","label":"Title","values":["Ube4B Levels Determine The Efficacy of Egfr and Stat5 Inhibitors In Treatment Resistant Neuroblastoma"]}]}],"canonical_facts":{"dc:contributor":["Andrew J. Bean, Ph.D.","Edgar T. Walters, Ph.D.","Shane R. Cunha, Ph.D."],"dc:creator":["Savage, David James","https://orcid.org/0000-0003-4690-5115
"],"dc:date.available":["2019-06-18T07:00:00Z"],"dc:description.abstract":["Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors can result in enhanced EGFR signaling, uncontrolled proliferation, and may provide a mechanism for chemotherapy resistance. UBE4B, an E3/E4 ubiquitin ligase, ubiquitinates the EGFR and promotes its lysosomal degradation ultimately attenuating EGFR signaling. Interestingly, the UBE4B gene lies in a chromosomal region (1p36) whose loss is correlated with poor patient outcomes due to inefficient EGFR degradation and enhanced cell proliferation. We examined whether depletion of UBE4B in a chemoresistant neuroblastoma cell line would affect tumor responses to drugs that specifically target selected proteins that are upregulated in the absence of UBE4B. UBE4B depletion in a resistant neuroblastoma cell line resulted in a number of proteins whose levels were altered, including an increase in EGFR and STAT5a levels. We observed that treatment with Cetuximab, a therapeutic antibody targeting the EGFR, significantly inhibited the proliferation of neuroblastoma cells depleted of UBE4B. Addition of a STAT5 inhibitor potentiated the Cetuximab-induced inhibition of proliferation, reduced migration, and enhanced apoptosis in UBE4B-depleted neuroblastoma cells more than either drug treatment alone. Thus, screening resected patient tumors for 1p36 status and UBE4B levels may enable a novel treatment strategy in which selected patients who have low UBE4B-expressing tumors may benefit from simultaneously targeting multiple EGFR signaling pathways.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/872"],"dc:subject":["Neuroblastoma","UBE4B","Cetuximab","STAT5","EGFR","Cancer Biology","Medicine and Health Sciences","Other Neuroscience and Neurobiology"],"dc:title":["Ube4B Levels Determine The Efficacy of Egfr and Stat5 Inhibitors In Treatment Resistant Neuroblastoma"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:30Z"}