DOI

https://doi.org/10.25772/CRST-XB73

Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Human Genetics

First Advisor

Senthil Radhakrishnan

Second Advisor

Swadesh Das

Third Advisor

James Lister

Fourth Advisor

Youngman Oh

Abstract

Proteasome inhibitors, such as carfilzomib, are FDA-approved to treat multiple myeloma and mantle cell lymphoma. Unfortunately, proteasome inhibitors have only produced clinically significant results in patients with hematologic cancers, despite their predicted pan-cancer utility, and even hematologic cancer types frequently show intrinsic and acquired resistance.

One proposed mechanism responsible for the proteasome inhibitors' shortcomings is the NRF1-mediated bounce-back response. Identification of drugs that can potentiate the action of proteasome inhibitors could overcome resistance in patients with hematologic cancers and expand proteasome inhibitors' use to treat solid tumors. Our previous studies have identified anthracyclines as potential compounds that interfere with the bounce-back response. Here, we found the mechanistic basics of which anthracyclines inhibit the bounce-back response. Anthracyclines were found to disrupt NRF1 binding to the antioxidant response element (the sequence where NRF1 binds to the DNA) of its targets, proteasome subunit genes. This disruption attenuated NRF1’s ability to activate proteasome genes in response to proteasome inhibition, impeding the bounce-back response and increasing the duration of proteasome inhibition experienced by cells. Finally, our work provides a mechanistic explanation behind the NRF1 and anthracyclines interaction in vitro and could prompt future preclinical and clinical studies to further investigate CFZ and anthracyclines as combinational therapy.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

11-28-2022

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