# SUMO Modification and Cancer Therapy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $412,437

## Abstract

Inhibiting the oncogene c-Myc and mutant KRas remains a major challenge in cancer research. c-Myc
and KRas are hyperactive in more than 70% of all human cancers, and contribute to resistance to
therapies. However, drugs that directly inhibit c-Myc or mutant KRas have not yet been developed. c-
Myc and KRas are key oncogenic drivers in colorectal cancer, a leading cause of cancer death; nearly
100% of colorectal cancers depend on c-Myc, while KRas mutations occur in ~50% of colorectal
cancers. Recent findings indicate that post-translational modification by the Small Ubiquitin-like
MOdifiers (SUMO) play a critical role in c-Myc and KRas-dependent oncogenesis; however, the
mechanisms of how SUMOylaton is involved in c-Myc and KRas-dependent oncogenesis are not well
understood. Wnt-signaling pathways could be a critical link of SUMOylation to both c-Myc activation and
KRas mutation in colorectal cancers. Dysregulated Wnt-signaling leads to increased c-Myc expression
and activity. In addition, KRas mutation suppresses the non-canonical Wnt signaling pathway, thereby
enhancing the canonical Wnt-signaling pathway. Wnt signaling is also key to maintaining the pool of
cancer stem cells in a wide range of cancers. During the previous funding period, we found that
inhibition of SUMOylation significantly suppressed Wnt down-stream targets, including c-Myc. Key
proteins, both in the canonical and non-canonical Wnt pathways, have been recently shown to be
substrates of SUMOylation. However, the current understanding of how SUMOylation regulates the Wnt
pathways is incomplete, and thus will be investigated here using colorectal cancer as a model system.
We will conduct a combination of structural studies and chemical synthesis to determine the mechanism
of allosteric inhibition by our lead small molecule SUMOylation inhibitor. We will conduct biochemical
and molecular biological studies to elucidate the mechanism of SUMOylation in the Wnt signaling
pathways. Finally, we will determine the therapeutic efficacy of our lead SUMOylation small molecule
inhibitor in c-Myc and KRas-dependent colorectal cancers. We expect that the proposed studies will lead
to a new paradigm by providing proof of principle for much-needed therapies that target c-Myc and KRas
and dysregulated Wnt-signaling. Our work will also have implications for the many other cancers that are
dependent on c-Myc and KRas.
!

## Key facts

- **NIH application ID:** 9858350
- **Project number:** 7R01GM086171-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Yuan Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,437
- **Award type:** 7
- **Project period:** 2008-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858350

## Citation

> US National Institutes of Health, RePORTER application 9858350, SUMO Modification and Cancer Therapy (7R01GM086171-12). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9858350. Licensed CC0.

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