Related Experiment Video

Updated: Jan 9, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.8K

CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen

Nealia C House1, Maxine M Chen2, Sima Khazaei3

  • 1Blueprint Medicines Corporation, Cambridge, MA, USA. NHouse@blueprintmedicines.com.

NPJ Breast Cancer
|December 3, 2025
PubMed

Insights

Combining CDK2 and CDK4/6 inhibitors shows promise against breast cancer resistance. This dual inhibition, along with endocrine therapy, demonstrated significant antitumor activity in preclinical models and early clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aberrant cyclin-dependent kinase 2 (CDK2) activity is a key resistance mechanism to CDK4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
  • Understanding resistance mechanisms is crucial for improving breast cancer treatment efficacy.

Purpose of the Study:

  • To evaluate the preclinical and clinical activity of combined CDK2 and CDK4/6 inhibition in breast cancer.
  • To identify predictive biomarkers for response to combined CDK inhibition.
  • To assess the potential of adding endocrine therapy to CDK inhibitor combinations.

Main Methods:

  • Utilized patient-derived xenograft models of HR+ and triple-negative breast cancer.
  • Developed and validated a novel mRNA expression signature (CCND1, CCNE1, RB1, CDKN2A) to predict response.
  • Administered combination therapies including CDK2 inhibitors (CDK2i), CDK4/6 inhibitors (CDK4/6i), and endocrine therapy.
  • Analyzed early clinical data from patients with HR+/HER2- breast cancer treated with BLU-222 (a CDK2i) in combination regimens.

Main Results:

  • The CDK2i + CDK4/6i combination demonstrated broad antitumor activity in both CDK4/6i-resistant and -naïve HR+ and triple-negative breast cancer models.
  • A weighted mRNA signature involving CCND1, CCNE1, RB1, and CDKN2A (p16) effectively predicted response to combined CDK inhibition.
  • Addition of endocrine therapy significantly enhanced antitumor activity in HR+ models.
  • Early clinical data showed activity of the CDK2 inhibitor BLU-222 as monotherapy and in combination with ribociclib and fulvestrant in HR+/HER2- breast cancer patients.

Conclusions:

  • Combined CDK2 and CDK4/6 inhibition can overcome resistance mechanisms to CDK4/6i in breast cancer.
  • The identified mRNA signature serves as a potential predictive biomarker for response to combined CDK inhibition.
  • Combination therapy including CDK inhibitors and endocrine therapy holds significant promise for treating HR+/HER2- breast cancer.

More Related Videos

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

11.4K
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

7.8K

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.5K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
6.2K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.6K
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
6.4K
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
9.3K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.7K