# Targeting c-Myc and Proteasome Inhibitor Resistance in Multiple Myeloma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $536,425

## Abstract

The discovery of new therapeutic targets for treating multiple myeloma (MM) and elucidating
their underlying molecular mechanisms are necessary for the progress in treatment of this
disease. Despite significant recent progress in treating MM, such as the use of proteasome
inhibitors, which have a > 70% response rate, the disease inevitably relapses and remains
incurable. The oncogene c-Myc is a key driver in MM; it is activated in more than 60% of MM
and in nearly 80% of proteasome inhibitor refractory MM. However, drugs that directly inhibit c-
Myc do not yet exist, largely because c-Myc is a transcription factor and lacks a defined three-
dimensional structure and pockets to which small molecules can bind. In addition to c-Myc,
MM cells are strongly dependent on the ubiquitin-proteasome system for survival, as
demonstrated by the proteasome inhibitors. In this proposal, we will test the hypothesis that
targeting post-translational modifications by the small ubiquitin-like modifier (SUMO) can inhibit
c-Myc-dependent pathways and also provide a means for overcoming proteasome inhibitor
resistance. The proposed studies are based on our preliminary findings that SUMO
modification regulates c-Myc protein levels and activity in MM cells. In addition, our preliminary
findings suggest that the mechanisms of bortezomib (proteasome inhibitor) resistance not only
could depend on SUMO modification, but also could render proteasome function more
dependent on SUMO modification in resistant than in sensitive MM cells. We propose to
elucidate the mechanism of how SUMOylation is involved in regulating c-Myc levels and
function. In addition, we will elucidate the role of SUMOylation in the poorly understood
mechanisms underlying proteasome inhibitor resistance. We will also validate initial in vitro
findings in animal models. These studies will be enabled by SUMO E1 inhibitors that we have
been developing over the last few years. The proposed studies will likely establish a novel
therapeutic target and mechanism for the treatment of MM by offering targeted therapies and
by providing therapeutic approaches to overcome resistance to proteasome inhibition.
Inhibition of SUMOylation could also address a large population of other cancers that resist
conventional therapies by developing drugs that are efficacious against c-Myc-driven cancers.

## Key facts

- **NIH application ID:** 9942394
- **Project number:** 5R01CA212119-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Yuan Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $536,425
- **Award type:** 5
- **Project period:** 2017-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942394

## Citation

> US National Institutes of Health, RePORTER application 9942394, Targeting c-Myc and Proteasome Inhibitor Resistance in Multiple Myeloma (5R01CA212119-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942394. Licensed CC0.

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