BOSTON, Sep 03: New research from Dana-Farber Cancer Institute scientists suggests that cyclin-dependent kinase 2 inhibitors, which are currently being tested as treatments that slow the growth of a narrow range of cancers, could potentially be more broadly applicable to a wide range of cancers when combined with immunotherapy.
According to the study, a combination of a CDK2 inhibitor plus an immune checkpoint inhibitor resulted in eradication of colorectal and breast cancers in animal models. Based on this research, the Dana-Farber team plans to test the concept in a clinical trial.
“CDK2 inhibitors are being tested in clinical trials now, primarily in forms of ovarian and breast cancer known to require CDK2 for cancer cell growth,” says co-senior author and Dana-Farber scientist Peter Sicinski, MD, PhD. “But we’ve found that CDK2 inhibitors can be used in a way we did not expect, to overcome resistance to immune checkpoint inhibitors.”
The paper was published in Molecular Cell.
CDK2 is a protein that is involved in the cell division process. It is activated by another protein called cyclin E. Several small-molecule CDK2 inhibitors are currently being tested in clinical trials for patients with forms of ovarian cancer and breast cancer that have cyclin E amplification and rely on CDK2 activity for growth.
First author Chen Chu, PhD, an instructor in medicine in the Sicinski Lab at Dana-Farber, wanted to learn more about the function of CDK2 beyond cell division. He eliminated CDK2 in cancer cells and observed gene expression changes that activate immune signaling, including genes known to be involved in how tumors respond to immunotherapy.
“The transcriptional changes were striking—the strongest effects involved genes that regulate interactions between tumor cells and the immune system,” says Chu. “This led us to ask whether CDK2 activity might contribute to resistance to immune checkpoint blockade.”
With more research, the team found that hyperactivated cyclin E–CDK2 in cancer cells phosphorylates the epigenetic regulator bromodomain-containing protein 4, restricting its occupancy on chromatin and reducing the expression of immune-related genes, including antigen processing and presentation genes, interferon-stimulated genes and other genes related to immune checkpoints. The team also found that these changes in immune-related gene expression enable tumors to resist immune checkpoint inhibitors.
To connect these molecular findings to human patients, Chu queried a database called the Cancer Immunology Data Engine which links immunotherapy outcomes in clinical trials to tumor gene-expression profiles. That query showed that high levels of expression of Cyclin E and CDK2 are associated with poor responses to immune checkpoint blockade.
“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,” says Sicinski. “Now we are finding it has additional consequences for tumors because it helps them evade immunotherapy.”
In animal models of colon cancer and breast cancer, the team found that genetic inactivation of CDK2 or treatment with the CDK2 inhibitor tegtociclib plus an immune checkpoint inhibitor dramatically increased the survival of the animals compared to either therapy alone, including in a model of triple-negative breast cancer that was completely resistant to immune checkpoint blockade. In animals that responded to the combination, tumors vanished.
Further study, with the aid of Dana-Farber cancer immunology expert and co-senior author Kai Wucherpfennig, MD, PhD, revealed that inhibiting CDK2 has a dual function. In addition to causing tumor cells to stop resisting immunotherapy, it also directly affects immune cells called dendritic cells. With CDK2 inhibition, dendritic cells increase in number and their infiltration into tumors increases. Dendritic cells also become more effective at picking up fragments of tumor cells, called antigens, and presenting them to T cells, which use them to find and kill other cancer cells.
“There are two independent mechanisms that the CDK2 inhibitor is influencing against cancer,” says Wucherpfennig. “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.”
In the study, an analysis of data from the Cancer Genome Atlas, a publicly available gene expression dataset from patients, cyclin E-CDK2 hyperactivation was associated with suppression of immune-related genes in a range of cancers, including bladder cancer, ovarian cancer, uterine cancer, colorectal cancer, liver cancer, lung cancer, lymphoma, melanoma and prostate cancer, suggesting that the strategy of sensitizing cancer to immunotherapy with CDK2 inhibition could be widely applicable.