New research from Dana-Farber Cancer Institute suggests that inhibiting cyclin-dependent kinase 2 (CDK2) could help overcome resistance to immune checkpoint inhibitors across many cancers.
In preclinical models of colorectal and breast cancer, combining a CDK2 inhibitor with immune checkpoint blockade significantly improved survival compared with either treatment alone. In responding animals, tumors were completely eradicated.
The findings, published in Molecular Cell, provide a new rationale for combining CDK2-targeted therapies with immunotherapy. Based on the results, the Dana-Farber researchers are planning to evaluate the approach in a clinical trial.
Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4
Authors: Chen Chu1, Shanshan Zheng, Ning Mitchell, et. al
Molecular Cell, September 02, 2026, DOI: 10.1016/j.molcel.2026.08.007
Peter Sicinski, MD, PhD, co-senior author of the study and a scientist at Dana-Farber, said:
“We’ve found that CDK2 inhibitors can be used in a way we did not expect, to overcome resistance to immune checkpoint inhibitors.”
CDK2 May Do More Than Drive Cancer Cell Division
CDK2 is a protein involved in cell division and is activated by cyclin E. Several small-molecule CDK2 inhibitors are already being investigated in clinical trials, particularly in ovarian and breast cancers with cyclin E amplification that depend on CDK2 activity for tumor growth.
However, the new study suggests that the cyclin E–CDK2 pathway also plays a role in helping tumors evade immune attack.
First author Chen Chu, PhD, an instructor in medicine in the Sicinski Lab at Dana-Farber, investigated what happens when CDK2 is eliminated from cancer cells. The researchers observed substantial changes in the expression of genes involved in immune signaling and tumor responses to immunotherapy. Talking about the findings, he said:
“The transcriptional changes were striking. The strongest effects involved genes that regulate interactions between tumor cells and the immune system. This led us to ask whether CDK2 activity might contribute to resistance to immune checkpoint blockade.”
The researchers found that hyperactivated cyclin E–CDK2 phosphorylates the epigenetic regulator BRD4, restricting its activity on chromatin and suppressing genes involved in antigen processing and presentation, interferon signaling and other immune-related pathways.
Analysis using the Cancer Immunology Data Engine further showed that high cyclin E and CDK2 expression was associated with poorer responses to immune checkpoint blockade.
Sicinski noted that the findings expand the understanding of cyclin E beyond its established role in driving cell proliferation, pointing to a potential role in tumor immune evasion.
“I’ve been studying Cyclin E for many years and always thought-and I think the field still thinks-of Cyclin E as a driver of cell proliferation. Now we are finding it has additional consequences for tumors because it helps them evade immunotherapy.”
CDK2 Inhibition Plus Immunotherapy Eliminated Tumors in Animal Models
In animal models of colon and breast cancer, genetic inactivation of CDK2 or treatment with the investigational CDK2 inhibitor tegtociclib combined with an immune checkpoint inhibitor substantially increased survival compared with either therapy alone.
The effect was also observed in a model of triple-negative breast cancer that was completely resistant to immune checkpoint blockade. Among animals that responded to the combination, tumors disappeared.
Further experiments led by co-senior author Kai Wucherpfennig, MD, PhD, showed that CDK2 inhibition appears to work through two separate mechanisms. In addition to making tumor cells more susceptible to immune checkpoint blockade, CDK2 inhibition increased the number of dendritic cells and their infiltration into tumors. The dendritic cells also became more effective at capturing tumor antigens and presenting them to T cells, helping activate an antitumor immune response. Wucherpfennig said:
“There are two independent mechanisms that the CDK2 inhibitor is influencing against cancer. One is on cancer cells themselves, making them more sensitive to immune checkpoint blockade, and the other is on dendritic cells, making them more active.”
Potential Across Multiple Cancer Types
The researchers also analyzed data from The Cancer Genome Atlas and found that cyclin E–CDK2 hyperactivation was associated with suppression of immune-related genes across multiple malignancies, including bladder, ovarian, uterine, colorectal, liver, lung and prostate cancers, as well as lymphoma and melanoma.
The findings suggest that targeting CDK2 may have applications beyond cancers currently being studied with CDK2 inhibitors and could potentially serve as a strategy for sensitizing tumors to immunotherapy.
The approach remains preclinical, and its safety and effectiveness in combination with immune checkpoint inhibitors will need to be established in patients. The Dana-Farber team now plans to move the concept toward clinical testing.
Read further on OncoDaily: CDK2 Inhibition in CDK4/6 – Resistant Breast Cancer: A New Escape Route Under Study
