CDK2 Cancer Drugs Could Work Far Beyond Their Original Target, Study Finds

Cyclin-dependent kinase 2, or CDK2, inhibitors are being tested in clinical trials for ovarian and breast cancers that depend on the CDK2 protein to grow. Now, Dana-Farber Cancer Institute researchers have found the drugs could be far more broadly useful: combined with an immune checkpoint inhibitor, a CDK2 inhibitor eradicated colorectal and breast cancers in animal models. The findings were published in the journal Molecular Cell, and the Dana-Farber team plans to test the approach in a clinical trial.

CDK2, a protein activated by another protein called cyclin E, normally drives cell division. Studying its role beyond cell division, first author Chen Chu removed CDK2 from cancer cells and found striking changes in gene activity, particularly in genes that govern how tumor cells interact with the immune system. That led the team to ask whether CDK2 might help tumors resist immune checkpoint blockade, a cancer treatment that releases the immune system's natural brakes so it can attack tumors.

The researchers found that when cyclin E and CDK2 are overactive, they alter an epigenetic regulator called BRD4 in a way that reduces the activity of immune-related genes, including ones that help the immune system recognize tumors. This lets cancer cells evade the immune system. "Now we are finding it has additional consequences for tumors because it helps them evade immunotherapy," said co-senior author Peter Sicinski.

In mouse models of colon and breast cancer, including a form of triple-negative breast cancer that fully resisted immune checkpoint blockade on its own, combining a CDK2 inhibitor with an immune checkpoint inhibitor dramatically increased survival, and tumors vanished in animals that responded. Co-senior author Kai Wucherpfennig said CDK2 inhibition works in two ways: it makes cancer cells more sensitive to immune checkpoint blockade, and it also increases the number and activity of dendritic cells, immune cells that pick up fragments of tumor cells and present them to T cells that then hunt down the cancer.

An analysis of patient gene-expression data found that cyclin E-CDK2 hyperactivation was linked to suppressed immune-related genes across many cancer types, including bladder, ovarian, uterine, colorectal, liver, lung, lymphoma, melanoma and prostate cancer, suggesting the approach could be widely applicable.