# Regulation of resistance to CDK4/6 inhibitor in breast cancer

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2023 · $650,485

## Abstract

Project Summary
Cyclin-dependent kinase CDK4/6 inhibitor (CDK4/6i) in combination with aromatase inhibitors is the first-line
treatment for ER+ advanced or metastatic breast cancer. Despite CDK4/6 inhibitors significantly improve
overall survival of such patients, not all patients respond to these drugs and most patients whose tumors
initially respond to CDK4/6i eventually develop acquired resistance. Although many efforts have been invested
into the studying mechanism of resistance, CDK4/6i resistance remains a big challenge for HR+ breast cancer.
Thus, it is urgent to develop new approaches to overcome resistance in CDK4/6i resistant breast cancer
(CRBC). O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is one type of glycosylation that occurs when a
monosaccharide, O-GlcNAc, is added onto serine or threonine residues of proteins by O-GlcNAc transferase
(OGT). O-GlcNAcylation is involved in a range of cellular activities and aberrant O-GlcNAcylation has been
implicated in a host of diseases including cancer. However, the role of O-GlcNAcylation in cancer drug
resistance remains largely unknown.
 Through an innovative quantitative high throughput combination screen (qHTCS) and follow-up
extensive preliminary studies using cellular and molecular approaches, we identified a novel OGT-mediated
mechanism regulating the resistance to CDK4/6i in ER+ breast cancer. The major objective of this proposal is
to determine the role of OGT-mediated pathway in the regulation of CDK4/6i resistance in CRBC cells.
Specifically, we will (1) investigate the molecular mechanism of how OGT-mediated pathway regulates
CDK4/6i resistance in CRBC cells, (2) evaluate the effects of newly identified drug combinational treatments on
palbociclib resistance using resistant PDX and syngeneic models, (3) conduct clinical study to further evaluate
the correlation between OGT-mediated pathway and CDK4/6i resistance in tumors from patients. The
completion of proposed studies will not only elucidate a novel mechanism regulating CDK4/6i resistance in
ER+ breast cancer, but also provide an innovative therapeutic strategy to treat CRBC patients.

## Key facts

- **NIH application ID:** 10560131
- **Project number:** 1R01CA275904-01
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Shunqiang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $650,485
- **Award type:** 1
- **Project period:** 2023-03-22 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10560131

## Citation

> US National Institutes of Health, RePORTER application 10560131, Regulation of resistance to CDK4/6 inhibitor in breast cancer (1R01CA275904-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10560131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*