Genetic variation enhances cancer drug sensitivity

The human genome is organised in 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 tumour formation, the cancer cells can end up with only the faulty gene.

"In cancer cells it is common that larger or smaller parts 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. 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," says Xiaonan Zhang, researcher at the Department of Immunology, Genetics and Pathology and first author of the study.

In the present study, the researchers analysed a large number of genes and identified one gene situated in 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 analysed 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The researchers' unpublished data also suggests that talazoparib may exhibit CYP2D6-dependent effects on neuroblastoma and ovarian cancer cells.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 analyse 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. This strategy has the potential to advance precision medicine, not only in cancer care but also in various other fields of healthcare. By aligning treatments with patients' specific genetic characteristics, more effective therapies can be developed and thereby improve disease, say Tobias Sjöblom, professor at Department of Immunology, Genetics and Pathology, who has led the study.

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