A research team has published a new study detailing how the breast cancer drug, palbociclib, drives cancer cells into senescence. It is already known that the small molecule inhibitor induces cell cycle arrest by blocking cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) signaling, however, it was unclear why inhibiting CDK4/6 would result in cell senescence. The study, published in The EMBO Journal, showed that the drug activates the 20S proteasome, a complex responsible for proteolytic degradation inside of cells.
The researchers used a novel technology called a mass spectrometry-based cellular thermal shift assay (MS-CeTSA) to measure to proteins inside MCF7 cells, a breast cancer cell line, after palbociclib treatment. The drug discovery technique detects proteins that bind directly to the drug or proteins that change their behavior in response to the drug. This approach clearly showed that palbociclib increases proteasome activity independently of the ubiquitin pathway by reducing association with ECM29, a proteolysis-inhibiting scaffold protein. Once detached from ECM29, the proteasome drives cellular senescence by degrading proteins required for cell cycle progression.
"While it was known that palbociclib stalls proliferation by inhibiting CDK4/6, inducing proteasomal activity may be an additional mechanism that ensures the completeness of the cell cycle arrest," says Mikael Björklund, one of the lead authors of the study.
Proteasomal activity must be tightly regulated to maintain normal cell cycle progression. Specific cell cycle regulatory proteins and cyclins must be degraded in order to keep up cellular homeostasis. The proteasome has been identified as a drug target for breast cancer treatments and the finding that palbociclib is an activator of its activity is important to consider when exploring various drug combinations.
"Our work suggests that proteasome inhibitors and palbociclib are a not a good combination, given that they act in opposite direction," says Matthias Trost, who led the study together with Björklund.