CDK2 inhibitor plus immunotherapy erased tumors in animal models

A triple-negative breast cancer model had been completely resistant to immune checkpoint blockade. When Dana-Farber researchers added the CDK2 inhibitor tegtociclib to an immune checkpoint inhibitor, tumors vanished in the animals that responded to the combination. The same pairing eradicated colorectal and breast cancers in animal models and dramatically improved survival over either treatment alone, the team reports in Molecular Cell.

That result pushes CDK2 beyond its familiar role in cell division. The protein is activated by cyclin E, and several small-molecule CDK2 inhibitors are already being tested in clinical trials, mainly for ovarian and breast cancers whose tumors have cyclin E amplification and depend on CDK2 to grow. Peter Sicinski, a Dana-Farber scientist and co-senior author, says the team found another use: overcoming resistance to immune checkpoint inhibitors.

The mechanism begins inside the tumor cell. When cyclin E–CDK2 is hyperactivated, it phosphorylates BRD4, an epigenetic regulator, restricting BRD4’s occupancy on chromatin and reducing the expression of immune-related genes. Those include genes for antigen processing and presentation, interferon-stimulated genes and other genes linked to immune checkpoints. A query of the Cancer Immunology Data Engine also found that high cyclin E and CDK2 expression was associated with poor responses to immune checkpoint blockade.

CDK2 inhibition has a second effect outside the cancer cell. The treatment increases the number of dendritic cells and their infiltration into tumors, while making them more effective at collecting tumor fragments, called antigens, and presenting them to immune cells called T cells. Kai Wucherpfennig, the study’s other co-senior author, describes these as two separate mechanisms: weakening the tumor’s resistance and strengthening the immune response.

Concretely, the near-term consequence is a proposed clinical trial, not a new treatment for patients today. The direct treatment results come from animal models, while the suggested reach across bladder, ovarian, uterine, colorectal, liver, lung, lymphoma, melanoma and prostate cancers comes from gene-expression associations in the Cancer Genome Atlas. Dana-Farber plans to test the combination in people; whether it improves immunotherapy response in patients remains untested in this study.