by Uppsala University

A graphical summary illustrates the strategy used to identify CYP2D6 as a target for collateral lethality, which is driven by the widespread occurrence of loss of heterozygosity in cancer genomes. Credit: Xiaonan Zhang

By exploiting the genetic variation in cancer cells, an already approved cancer drug demonstrated enhanced effects against cancer cells in specific patient groups. This is shown in a study by Uppsala University, published in the journal eBiomedicine. The findings suggest a potential for more individually tailored and more effective cancer therapies.

The human genome is organized into 46 chromosomes, where all but the X and Y chromosomes in men are present in two copies. This means that a person with a faulty gene on one chromosome most often has a functional version on the other. But during tumor formation, the cancer cells can end up with only the faulty gene.

"In cancer cells it is common that larger or smaller parts of the chromosomes are lost. If the faulty gene variant is the one that is retained, the cancer cells will lack the protein that was supposed to be produced from this gene," says Xiaonan Zhang, researcher at the Department of Immunology, Genetics and Pathology and first author of the study.

"This is called loss of heterozygosity and it creates distinct differences between cancerous and normal cells. These differences have the potential to inform the development of treatments that specifically target cancer cells."

In the present study, the researchers analyzed a large number of genes and identified one gene situated in a DNA region that is commonly lost in various cancer types. The gene encodes an enzyme in the liver called CYP2D6. Subsequently, they tested different drug compounds on engineered cell models to determine how the effect of the compound was influenced by CYP2D6 activity.

"We analyzed drug compounds that are currently in clinical use or undergoing clinical trials. Among the most promising was a clinically approved drug called talazoparib, which consistently showed a heightened cytotoxic effect against liver cancer cells that lacked a functional CYP2D6 enzyme," says Xiaonan Zhang.

The researchers' unpublished data also suggests that talazoparib may exhibit CYP2D6-dependent effects on neuroblastoma and ovarian cancer cells. They will therefore further analyze drugs that target enzymes in other organs where enzyme activity levels vary.

"We believe that by leveraging loss of heterozygosity and natural genetic variations in the cancer cells, we can uncover new treatment options that lead to targeted therapies tailored to each patient's unique genetic profile," said Tobias Sjöblom, professor at the Department of Immunology, Genetics and Pathology, who led the study.

"This strategy has the potential to advance precision medicine, not only in cancer care but also in various other fields of health care. By aligning treatments with patients' specific genetic characteristics, more effective therapies can be developed and thereby improve disease."

The study was conducted in collaboration with researchers from Switzerland and the Chemical Biology Consortium Sweden (CBCS).

More information: Xiaonan Zhang et al, Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib, eBioMedicine (2024). DOI: 10.1016/j.ebiom.2024.105368

Journal information: EBioMedicine 

Provided by Uppsala University