Changes in the chromosomes of cancer cells may increase their sensitivity to anticancer drugs

Two complementary studies conducted by Tel Aviv University’s Faculty of Medical and Health Sciences, in collaboration with the European Institute of Oncology in Milan, have taken an in-depth look at the characteristics of cells with an abnormal number of chromosomes – called aneuploid cells – and reported findings that could advance new cancer treatments.

According to the researchers, “A significant proportion of cancer cells are aneuploid, which distinguishes them from healthy cells. Our work focuses on the vulnerabilities of aneuploid cells, with the aim of promoting new strategies to eliminate cancer tumors. In our studies, we found that aneuploidy increases the sensitivity of cancer cells to certain types of anticancer drugs.”

The studies were conducted by Prof. Uri Ben-David and PhD student Johanna Zerbib from the Department of Human Molecular Genetics and Biochemistry at Tel Aviv University’s Faculty of Medical and Health Sciences, in collaboration with Prof. Stefano Santaguida and PhD student Marica Rosaria Ippolito from the University of Milan in Italy, as well as researchers from both labs. Other contributors included research teams from Israel, Italy, the United States and Germany.

Two articles based on the research have been published in the journals Discovery of cancer And Communication about nature.

Professor Ben-David explains: “In the nucleus of a healthy human cell, there are 23 pairs of chromosomes, half from the father and half from the mother, for a total of 46. One of the characteristics of cancer cells, which distinguishes them from healthy cells, is an abnormal number of chromosomes, resulting from incorrect cell division, a phenomenon known as aneuploidy. We believe that if we can identify the specific vulnerabilities of aneuploid cells, we can promote new cancer treatments that target these weaknesses and do not harm healthy cells.”

“About three years ago, we published a comprehensive study in the journal Naturein which we classified about 2,000 malignant cells from different cancer types according to their level of aneuploidy and examined how they responded to various existing treatments. In this study, we discovered new vulnerabilities of aneuploid cells. However, the study had a limitation: because the cells came from different cancer types, it was difficult to isolate the impact of aneuploidy itself from the effect of other genetic differences between the tumors.

The researchers therefore chose to conduct a new study using cultures of human cells that were all genetically identical (i.e., from the same individual). They added a substance to the cultures that disrupts the separation of chromosomes, causing some of them to become aneuploid. Since the cells were genetically identical, the only difference between them after the procedure was the level of aneuploidy, i.e., the number of chromosomes.

To examine the effects of aneuploidy in depth, the cells underwent various characterization processes: DNA and RNA sequencing, measuring levels of all the proteins in the cell, assessing response to 6,000 different drugs, and a process known as CRISPR screening, which involves systematically altering every gene in the genome to identify essential genes in the cells.

The researchers noted: “In this way, a large and unique database of aneuploid cell characteristics has been established, which can serve as a basis for future studies, as well as the development of biological markers that predict the responses of cancer patients to specific drugs and treatments.”

In this in-depth study, a mechanism called MAPK (mitogen-activated protein kinase) was observed, which is particularly crucial for DNA damage repair in aneuploid cells. The study also showed that this mechanism is relevant for various types of aneuploid cells, including cancer cells in culture and in human tumors.

Professor Ben-David said: “We found that aneuploid cancer cells increase the activity of DNA repair mechanisms because of the large amount of DNA damage present; and we have discovered a mechanism that could allow us to exploit this characteristic to target these cancer cells.”

To test their hypothesis, the researchers disrupted the MAPK pathway in cells and then examined their sensitivity to chemotherapy. The results were promising: Aneuploid cells in which this mechanism was disrupted were much more sensitive to chemotherapy (which causes DNA damage) than cells with a normal number of chromosomes.

The researchers then sought to determine whether there was a correlation between this pathway and the clinical response of cancer patients to chemotherapy treatments. To do this, they relied on data from clinical treatments and experiments where human tumors were implanted in mice, and the results were clear: the higher the activity of the pathway in aneuploid tumors, the greater their resistance to chemotherapy.

The complete characterization of aneuploid cells also revealed another important discovery: these cells, which contain more chromosomes than normal cells, also necessarily contain a greater amount of DNA, which leads to an excessive production of RNA and proteins. The cell, seeking to compensate for this overproduction, tries to silence and degrade the excess RNA and proteins.

Johanna Zerbib noted: “Here we discovered another vulnerability of aneuploid cells, based on our hypothesis that these cells are more sensitive to existing drugs that inhibit protein degradation. To validate this hypothesis, we exposed cell cultures to these drugs and analyzed clinical data from patients treated with a drug that inhibits protein degradation in cells. The results confirmed the hypothesis that aneuploidy increases the sensitivity of cancer cells to these drugs.”

Professor Ben-David concludes: “In our research, we have identified two important vulnerabilities that characterize aneuploid cells, cells with chromosomal changes that are commonly found in cancer cells. The first is a mechanism essential for DNA damage repair, the alteration of which significantly increases the sensitivity of aneuploid cells to chemotherapy; the second is the increased degradation of excess RNA and proteins, which can be targeted, among other things, with inhibitors already used in the clinic.

“We have also created a large database of aneuploid cell characteristics that can be used to predict cancer patients’ responses to various drugs and treatments. We believe that the results of our research will benefit many researchers, oncologists and patients in the years to come.”