CDK2 inhibition may have potential for treating lung and other cancers

Many cancer cells–and lung cancers in particular–have an abnormal number of chromosomes, a feature that can help shield them from therapeutic attack. But now scientists are exploring ways to turn the tables and use this abnormality as a weapon against cancer. 

In a recent example of this, scientists at the Frederick National Laboratory for Cancer Research (FNL) found that by inhibiting the cell-cycle regulator CDK2 (cyclin-dependent kinase 2) it is possible to force a chromosomally abnormal cancer cell to divide in such a way that its progeny cannot survive. The daughter cells die in what is called anaphase catastrophe.  

The original experiments were conducted in mice. Since then, many CDK2 inhibitors have been shown to cause anaphase catastrophe, and several of these are in clinical testing as potential treatments for human cancers. In marked contrast, this death program was not observed in CDK2-inhibited normal human alveolar epithelial cells that line the respiratory tract.

In a follow-on study, the FNL group identified in greater detail what happens to cancer cells following CDK2 inhibition, information that could help hone potential future treatments for lung and other cancers.  

Using focused ion beam scanning electron microscopy (FIB-SEM), the researchers detected both chromosome rings and multipolar mitoses in aneuploid cancer cells treated with the CDK2 inhibitor CYC065.    

Chromosome rings occur when chromosomes break, and the loose ends attach to one another forming circular structures. This can lead to failed cancer cell division and cell death.  

In normal mitosis, two centrosomes aligned at opposite sides of the cell pull duplicated chromosomes toward them before the cell divides in two, forming two duplicated cells. Multipolar mitosis occurs in abnormal cells that have multiple centrosomes that pull chromosomes in many directions before the cell divides. This can cause immediate cell death or result in abnormal daughter cells, some of which do not survive. 

The research group also found that CDK2 inhibitors spare normal cells from induced cell death while preferentially damaging cancer cells.  This is a desirable therapeutic property as investigators explore CDK2 inhibitors as cancer treatments. 

The research was published in the journal Cancer Biology & Therapy and led by FNL Laboratory Director Ethan Dmitrovsky, M.D. with collaborators including Kedar Narayan, Ph.D., of the National Cancer Institute’s Center for Molecular Microscopy, as well as coauthor Xi Liu, Ph.D. and first author Zibo Chen, Ph.D., both of the Molecular Pharmacology Program at FNL.