# Characterizing Regulatory Mechanisms Underlying Drug Resistance in Breast Cancer Using Keratin 19

> **NIH NIH R15** · CATHOLIC UNIVERSITY OF AMERICA · 2022 · $473,458

## Abstract

PROJECT SUMMARY
Drug resistance continues to be the major limiting factor in achieving cures for cancer patients. In breast
cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have been approved recently to treat patients
with advanced estrogen receptor-positive tumors. However, most patients exhibit resistance due to a lack of
predictive biomarker. Understanding the molecular basis underlying drug resistance is required to provide a
critical breakthrough in identifying a predictive biomarker and developing effective therapeutic strategies.
Based on our previous work and preliminary data, we propose that a cytoskeletal protein keratin 19 (K19),
which currently serves as one of the most reliable diagnostic and prognostic markers, regulates signaling
events to impact resistance against CDK4/6 inhibitors. We found that K19 binds to and inhibits a
multifunctional kinase GSK to stabilize a CDK4/6 partner cyclin D3 in breast cancer cells. K19-GSK3
interaction was associated with decreased accumulation of GSK3 in the nucleus that is crucial to GSK3
function. Moreover, K19 promoted proliferation and maintained the sensitivity of cells to CDK4/6 inhibitors. We
hypothesize that cyclin D3 stabilized by K19-dependent inhibition of GSK3 causes tumors to become
dependent on the CDK4/6 pathway for growth and sensitizes them to CDK4/6 inhibitors. At the molecular level,
we surmise that K19 filaments serve as cytoplasmic scaffolds for GSK3 to prevent its entry into the nucleus
where it phosphorylates cyclin D3 for degradation. To address our hypotheses, we propose to 1) determine
K19 effects on the GSK3 signaling network, 2) characterize the interaction between K19 and GSK3, and 3)
determine the impact of K19 on drug resistance and tumor growth. To this end, in Aim 1, we will identify
upstream regulators of K19-GSK3 interaction as well as GSK3 targets whose activities affect K19-
dependent phenotypes. In Aim 2, GSK3-binding deficient K19 mutant will be characterized to determine how
K19 interacts with GSK3 and affects the nuclear entry of GSK3. In Aim 3, we will assess how K19 affects
sensitivities of various breast cancer subtypes to CDK4/6 inhibitors and test the role of K19 and GSK3 on the
sensitivity of tumors to a CDK4/6 inhibitor in vivo. Upon successful completion, the knowledge gained from the
study can help design new drugs targeting K19-dependent signaling pathways, establish K19 as a predictive
biomarker for response to CDK4/6 inhibitors, and develop effective therapeutic strategies to combat drug
resistance.

## Key facts

- **NIH application ID:** 10358875
- **Project number:** 1R15CA267890-01
- **Recipient organization:** CATHOLIC UNIVERSITY OF AMERICA
- **Principal Investigator:** John Sing Choy
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $473,458
- **Award type:** 1
- **Project period:** 2022-06-02 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358875

## Citation

> US National Institutes of Health, RePORTER application 10358875, Characterizing Regulatory Mechanisms Underlying Drug Resistance in Breast Cancer Using Keratin 19 (1R15CA267890-01). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10358875. Licensed CC0.

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