# Molecular basis of cell-cycle plasticity and robustness

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2024 · $383,891

## Abstract

Project Summary
 The mammalian cell cycle is commonly conceived as a well-understood, hardwired,
invariant pathway. Emerging work, however, indicates that the cell cycle is much more plastic
than generally believed, with multiple adaptive routes through the cell cycle under different
conditions. This plasticity makes the cell cycle robust to environmental perturbations, but also
drives adaptive drug resistance to targeted cell-cycle inhibitors. A fresh look at the dynamics and
pliability of cell-cycle progression will reveal new principles that predict dependence on a
particular cell-cycle node and new strategies to suppress adaptive cell-cycle rewiring.
 Cyclin-Dependent Kinases (CDKs) are key enzymes that drive cell proliferation, and
consequently, multiple CDK inhibitors are in development to suppress unwanted cell proliferation.
However, cells eventually find a way around these drugs to resume proliferation. A plausible
hypothesis is that cells leverage cell-cycle plasticity to pursue alternative paths through the cell
cycle. In one striking example, inhibition of CDK2 leads to rapid loss of substrate phosphorylation
as expected, but then CDK2 substrate phosphorylation rebounds within several hours. This
rebound depends on CDK4 and CDK6, which insulate the cell from fluctuations in CDK2 activity
by maintaining Rb hyper-phosphorylation and E2F transcription. This enables CDK2 re-activation
and eventual cell-cycle completion, even in the presence of potent CDK2 inhibitors.
 My lab has pioneered the development of a set of powerful time-lapse microscopy tools
to visualize rapid drug responses in single, living cells. Here, we will apply our technology to
determine the mechanisms driving this unusual rebound in CDK2 activity observed upon CDK2
inhibition. First, we will test the role of the p16 CDK4/6 inhibitor protein on the CDK2 activity
rebound. Second, we will test whether CDK2-dependent degradation of Cyclin D modulates the
CDK2 activity rebound. Third, we will identify additional mechanisms underlying the robustness
of Rb phosphorylation to inhibition of CDK2 and show how long-term drug pressure unleashes
the plasticity of CDKs. Since our findings are likely to be broadly applicable beyond CDK2
inhibitors, our proposed work will fill long-standing gaps in our understanding of how the cell cycle
is wired for success in the face of perturbations.

## Key facts

- **NIH application ID:** 10981127
- **Project number:** 1R01GM152642-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Sabrina Leigh Spencer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,891
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981127

## Citation

> US National Institutes of Health, RePORTER application 10981127, Molecular basis of cell-cycle plasticity and robustness (1R01GM152642-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981127. Licensed CC0.

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