'Achilles' heel' of cancer cells revealed

A new study from Tel Aviv University (TAU) shows, for the first time, how an abnormal number of chromosomes (aneuploidy) -- a unique characteristic of cancer cells that researchers have known about for decades -- could become a weak point for these cells. The study could lead to the development of future drugs that will use this vulnerability to eliminate the cancer cells.

The study was conducted in the laboratory of Dr. Uri Ben-David of TAU's Sackler Faculty of Medicine, in collaboration with six laboratories from four other countries. It was published in the journal Nature on January 27, 2021.

Aneuploidy is a hallmark of cancer. Normal human cells contain two sets of 23 chromosomes each, one from the father and one from the mother. But aneuploid cells have a different number of chromosomes. When aneuploidy forms in cancer cells, the cells not only "tolerate" it, but it can even advance the progression of the disease. The relationship between aneuploidy and cancer was discovered over a century ago, long before it was known that cancer was a genetic disease and even before the discovery of DNA as hereditary material.

According to Dr. Ben-David, aneuploidy is the most common genetic change in cancer. Approximately 90% of solid tumors, such as breast cancer and colon cancer, and 75% of blood cancers are aneuploid in nature. But researchers' understanding of the how aneuploidy contributes to the development and spread of cancer has been limited.

In the study, the researchers used advanced bioinformatics methods to quantify aneuploidy in approximately 1,000 cancer cell cultures. They then compared the genetic dependency and drug sensitivity of the cells with a high level of aneuploidy to those of the cells with a low level of aneuploidy.

They found that aneuploid cancer cells demonstrate heightened sensitivity to damage to the mitotic checkpoint -- a cellular checkpoint that ensures the proper separation of chromosomes during cell division. They also discovered the molecular basis for the heightened sensitivity of aneuploid cancer cells.

The study has important implications for the drug discovery process in personalized cancer medicine. Drugs that delay the separation of chromosomes are undergoing clinical trials, but it is not known which patients will respond to them and which will not. The results of this study suggest that it will be possible to use aneuploidy as a biological marker to identify patients who will respond better to these drugs.

"It should be emphasized that the study was done on cells in a culture and not on cancer patients. In order to translate it to treatment of cancer patients, many more follow-up studies must be performed. Still, even at this stage it is clear that the study could have a number of medical implications," Dr. Ben-David says.