Breast cancer cells that metastasize to the brain are often fatal, and few effective therapies are available. In a recent study published in Nature Cell Biology, Yuzhalin et al. identified the cyclin-dependent kinase CDK5 as a potential therapeutic target for these brain metastases. Out of all cyclin-dependent kinase genes, CDK5 was the most upregulated in human brain metastases compared to matched breast cancer samples. The authors observed that reducing CDK5 expression in metastatic breast cancer cells could improve survival in immunocompetent mice. Furthermore, brain metastases promoted secretion of the extracellular matrix protein emilin-1 in astrocytes. In turn, astrocytic emilin-1 induced CDK5 expression in brain metastases, which ultimately enabled these cancer cells to evade the host immune response by inhibiting the MHC-I antigen-presentation pathway. Building on these results, the authors showed that treatment with a CDK5 inhibitor combined with an immune checkpoint inhibitor in mice promoted anti-cancer immune responses and limited the severity of brain metastases. These results suggest that astrocytic CDK5 may support the establishment of brain metastases and may be a future target for cancer treatment.

Original reference: Nat. Cell Bio. 26, 1773–1789 (2024)