Researchers at Tel Aviv University found that aneuploid cancer cells are more sensitive to certain anti-cancer drugs, revealing potential targets for new treatments.
Cancer cells with an abnormal number of chromosomes, known as aneuploid cells, were extensively examined, uncovering findings that may advance cancer treatment, two studies from Tel Aviv University and the European Institute of Oncology showed.
The researchers found that a significant number of cancer cells are aneuploid, and that they are more vulnerable than healthy cells. They also discovered that aneuploidy increases the sensitivity of cancer cells to certain anticancer drugs, potentially leading to new strategies for targeting and eliminating tumors.
“In our studies, we found that aneuploidy increases the sensitivity of cancer cells to certain types of anticancer drugs,” the researchers stated.
The studies were conducted by Prof. Uri Ben-David and doctoral student Johanna Zerbib from Tel Aviv University, in collaboration with Prof. Stefano Santaguida and doctoral student Marica Rosaria Ippolito from the University of Milan, along with teams from Israel, Italy, the USA, and Germany. Their research resulted in two articles published in the journals Cancer Discovery and Nature Communications.
Prof. Ben-David explained that healthy human cells have 46 chromosomes, while cancer cells often exhibit an abnormal number due to improper division, a condition known as aneuploidy.
He believes that identifying specific vulnerabilities in aneuploid cells could lead to targeted cancer treatments that spare healthy cells.
Previous studies
Three years ago, Prof. Ben-David’s team published a study classifying approximately 2,000 malignant cells by their aneuploidy levels and assessing their responses to various treatments. However, this study had limitations because the cells came from different cancer types, making it difficult to isolate the effects of aneuploidy from other genetic differences.
In their new study, the researchers used genetically identical human cell cultures to investigate aneuploidy. They introduced a substance that disrupted chromosome separation, creating cells with varying levels of aneuploidy.
This setup allowed for a focused examination of aneuploidy’s effects through DNA and RNA sequencing, protein level measurement, drug response testing on 6,000 drugs, and CRISPR screening to identify essential genes.
They created a comprehensive database of aneuploid cell characteristics, which could aid in future research and the development of biomarkers to predict cancer patients’ responses to treatments.
The study also examined the MAPK (mitogen-activated protein kinase) mechanism, which is crucial for repairing DNA damage in aneuploid cells. This mechanism was found to be relevant across various aneuploid cell types, including cancer cells in cultures and human tumors. Prof. Ben-David noted that aneuploid cancer cells show increased DNA repair activity due to significant DNA damage, suggesting a potential strategy to target these cells.
To test this hypothesis, the researchers disrupted the MAPK pathway in aneuploid cells and assessed their sensitivity to chemotherapy. They found that these disrupted cells were significantly more sensitive to chemotherapy, which induces DNA damage, than cells with a normal chromosome number.
To explore the correlation between MAPK activity and clinical chemotherapy responses, they analyzed data from clinical treatments and experiments involving human tumors implanted in mice. The results indicated that higher MAPK pathway activity in aneuploid tumors correlated with greater resistance to chemotherapy.
Characterizing aneuploid cells revealed that their excess chromosomes increase DNA, RNA, and protein production. These cells attempt to silence and degrade the surplus RNA and proteins to manage this overload. Johanna Zerbib noted that this creates a vulnerability, as aneuploid cells are more sensitive to existing drugs that inhibit protein degradation, a hypothesis that testing confirmed.
Prof. Ben-David emphasized two main vulnerabilities of aneuploid cells: heightened sensitivity to chemotherapy when DNA repair mechanisms are impaired and increased susceptibility to protein degradation inhibitors.
The research also established a comprehensive database of aneuploid cell characteristics, which could aid in predicting cancer patients’ responses to treatments, potentially benefiting future researchers, oncologists, and patients.
