# Cancer Hijacks Enzyme Substrate Mutations to Facilitate Tumorigenesis

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $181,741

## Abstract

PROJECT ABSTRACT
Genetic information codes for life events including disease associated changes and hints for cancer treatments.
A daunting task is to decode genetic information. A common approach is to investigate whether genetic changes
in cancer are associated with tumorigenesis. Efforts have been devoted to identifying key gene
amplification/deletion/fusion events and elucidating hot mutation-associated enzymatic changes and interactome
changes. However, mutations on enzymes only account for a small portion of total mutational landscape and
meanings of the majority of non-enzyme mutations remain unclear. To this end, we have developed an algorithm
to mine the gain or loss of key enzyme substrate motifs targeting the understudied non-enzyme mutations from
TCGA database, through which key enzyme functions can be altered. As a proof-of-principle study, using this
approach we have identified 1,792 mutations in cancer that a new motif for the AGC kinases is lost. These
mutations are more enriched in colon and esophageal carcinoma to more likely affect cellular signaling pathways.
More importantly, we validated that one hit, BUD13, upon mutation can bypass its phosphorylation by one AGC
kinase GRK6, through which these cancerous BUD13 mutations deficient in phosphorylation gain oncogenicity
to promote colon cancer growth through elevating the mTORC1 signaling. In this proposal, we will systematically
identify the first mutational landscape for all characterized enzyme motifs and further validate important hits using
an experimental pipeline that we have expertise on. We will also examine new therapeutic directions associated
with both WT- and mutant-BUD13 expressing colon cancer in both in vitro cell culture models and in vivo
preclinical animal models. We hope that our study will provide novel insights for mutations cancer hijacks to
promote tumorigenesis with the potential for patient stratification and cancer treatment.

## Key facts

- **NIH application ID:** 10435664
- **Project number:** 1R21CA270967-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Pengda Liu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $181,741
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435664

## Citation

> US National Institutes of Health, RePORTER application 10435664, Cancer Hijacks Enzyme Substrate Mutations to Facilitate Tumorigenesis (1R21CA270967-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10435664. Licensed CC0.

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