# The mechanism and consequences of MCM degradation induced by CDK4/6 inhibition

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $33,621

## Abstract

Project Summary
Cancer results from dysregulated cell cycle progression and uncontrolled cell division. Most tumors alter the
CDK4,6/RB/E2F pathway to promote oncogenesis, making it a promising therapeutic target. When coupled with
anti-hormone therapy, CDK4/6 inhibitors significantly improve the prognosis of patients with estrogen receptor
(ER)-positive/Her2-negative breast cancer. Nevertheless, the clinical use of CDK4/6 inhibitors is restricted by
dose-limiting toxicities and resistance. Thus, a better understanding of the mechanism of action of CDK4/6
inhibitors is required to maximize their therapeutic efficacy. The central goal of this proposal is to examine
changes in the stability of the minichromosome maintenance (MCM) complex proteins induced by
CDK4/6 inhibition (CDK4/6i). MCM is an essential DNA replication protein and its dysregulation can result in
replication stress, DNA damage, and cancer. To avoid this, the cellular localization of MCM is highly regulated
throughout the cell cycle, however, the protein abundance remains constant. Surprisingly, we discovered that
CDK4/6 inhibitors result in proteasome-dependent degradation of MCM in both untransformed epithelial cells
and in breast cancer cells. To our knowledge, this represents the first known mechanism of regulating MCM
abundance through active protein degradation. It thus remains unclear why a CDK4/6i-induced cellular arrest,
but not other forms of arrest such as quiescence, leads to active MCM degradation. In Aim 1 of this proposal,
we will determine the mechanism and consequences of CDK4/6i-induced MCM degradation by identifying the
E3 ubiquitin ligase(s) that tags MCM for degradation and by defining the precise target of ubiquitination. In our
initial discovery, we associated CDK4/6i-induced MCM degradation with replication stress and DNA damage,
but did not directly implicate MCM degradation as the primary source. We will test the hypothesis that MCM
degradation is a key source of CDK4/6i-induced replication stress and DNA damage by preventing its
degradation and determining if this prevents the accumulation of these phenotypes upon release from CDK4/6
inhibition. The results of these experiments will provide insight into whether MCM degradation can be exploited
to increase the cellular death-inducing capabilities of CDK4/6 inhibitors. In Aim 2, we will test the hypothesis that
CDK4/6i-induded MCM degradation results from altered RB/E2F-mediated gene expression. We have already
discovered that MCM degradation is RB-dependent, however, it is still unclear if it is E2F-dependent. To test
this, will first determine if CDK4/6i-induced MCM degradation results directly from repressed E2F activity. If so,
we will manipulate the expression of downstream E2F-regulated genes to elucidate the regulatory pathway(s)
that results in MCM degradation. If MCM degradation is E2F-independent, we will probe alternative mechanisms
by which RB mediates this phenotype. Taken together, these aims ...

## Key facts

- **NIH application ID:** 10387685
- **Project number:** 1F31CA268866-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Brandon Lee Mouery
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,621
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387685

## Citation

> US National Institutes of Health, RePORTER application 10387685, The mechanism and consequences of MCM degradation induced by CDK4/6 inhibition (1F31CA268866-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10387685. Licensed CC0.

---

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