Ube4B Levels Determine The Efficacy of Egfr and Stat5 Inhibitors In Treatment Resistant Neuroblastoma

<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>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2018

Authors dc:creator

• Savage, David James
• <p>https://orcid.org/0000-0003-4690-5115</p>

Contributors dc:contributor

• Andrew J. Bean, Ph.D.
• Edgar T. Walters, Ph.D.
• Shane R. Cunha, Ph.D.

• Neuroblastoma
• UBE4B
• Cetuximab
• STAT5
• EGFR
• Cancer Biology
• Medicine and Health Sciences
• Other Neuroscience and Neurobiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/872

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1917