# Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors

> **NIH NIH R37** · UNIVERSITY OF LOUISVILLE · 2021 · $356,850

## Abstract

We have recently discovered a novel oncogenic mechanism whereby cyclin D1 bypasses CDK4/6 inhibition
resulting in the stimulation of 6-phosphofructo-2-kinase (PFKFB3) and glucose metabolism. The objective of this
proposal is to characterize the role of PFKFB3 in mediating adaptation or resistance to CDK4/6 inhibition and to
define new approaches to increase the efficacy of CDK4/6 inhibitors in order to enable durable responses in
stage IV HR+ breast cancer patients. Deregulation of the estrogen receptor (ER)-cyclin D1-CDK4/6 pathway is
a hallmark of ER+ breast cancer that has prompted the development of CDK4/6 inhibitors. Although
administration of CDK4/6 inhibitors to patients with ER+ advanced breast cancers have resulted in an
improvement in progression free survival, almost all patients invariable develop resistance and relapse over time.
Activation of glucose metabolism upon CDK4/6 inhibition is becoming increasingly evident. A key stimulator of
glycolysis is the PFKFB3 enzyme which synthesizes fructose 2,6-bisphosphate (F2,6BP), a potent allosteric
activator of the rate-limiting 6-phosphofructo-1-kinase (PFK1). F2,6BP controls flux throughout the entire
glycolytic pathway and, as a result is required for the proliferation of cancer cells. In preliminary studies, we
provide evidence that PFKFB3 expression and activity is increased in response to CDK4 inhibition in ER+ breast
cancer cells and breast cancer patient tumors. Notably, we show that a PFKFB3 inhibitor, PFK-158, increases
the anti-tumor activity of anti-CDK4 targeted therapy in vitro and in vivo. We postulate that PFKFB3 is an
essential regulatory effector of the cyclin D1-CDK4/6 axis that serves to attenuate CDK4/6 inhibition effects by
stimulating glucose metabolism. Furthermore, we hypothesize that genetic or pharmacological inhibition of
PFKFB3 will increase the efficacy of CDK4/6 inhibitors by disabling the ability of the cell to sustain sufficient
glucose metabolism necessary for survival and growth. Aim 1 will determine the mechanism by which CDK4/6
inhibition induces PFKFB3 expression. Aim 2 will determine the effects of combined CDK4/6 and PFKFB3
inhibition on glucose metabolism, cell cycle, growth and survival in vitro. Aim 3 will examine the metabolic and
growth effects of pharmacological CDK4/6 and PFKFB3 inhibition as monotherapies and in combination in
mouse models of breast cancer in vivo. We anticipate that our studies will support the clinical testing of PFKFB3
inhibitors in combination with CDK4/6 inhibitors to increase the survival of advanced ER+ breast cancer patients.

## Key facts

- **NIH application ID:** 10213670
- **Project number:** 5R37CA234002-02
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** YOANNIS IMBERT-FERNANDEZ
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2020-07-09 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213670

## Citation

> US National Institutes of Health, RePORTER application 10213670, Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors (5R37CA234002-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10213670. Licensed CC0.

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