University of Eastern Finland discovers: Probing drug response at the cellular level opens up new opportunities for leukemia treatment

A recent study found an evasive movement in cancer cells, thanks to which some cells survive drug therapy targeting the cell cycle in acute lymphoblastic leukemia.

However, effective drug response has been achieved by sequentially targeting multiple drugs to cell cycle and cellular regulatory programs.

In collaboration with the University of Eastern Finland, Karolinska Institutet, Lund University and the University of Tampere The results of the study are published in the journal Genome Biology.

B-cell lymphoblastic leukemia (B-ALL) is the most common childhood cancer. About 30 percent of childhood cancers are of this type. About 15-20 percent of patients do not have an adequate therapeutic response with current chemotherapy, in which case the disease may come back. Additionally, long treatment protocols cause life-threatening complications in nearly 80 percent of all childhood cancer patients by age 45.

Despite the promises of precision medicine, the heterogeneity of cancer cells limits treatment options.

“In this study, with the help of new single-cell genetic methods and detailed biochemical and genetic analyses, we were able to shed light on the link between drug therapy and cellular heterogeneity. Therefore, we also demonstrate that drug therapy that sequentially targets cell cycle and gene regulatory programs can effectively prevent cancer cells from developing resistance to therapy. can show,” says the doctoral researcher. Come to Lahnalambi from the Department of Biomedical Sciences, University of Eastern Finland.

In the study, the treatment targeted the WEE1 kinase, a key regulatory protein at cell cycle checkpoints. Several drugs that affect the cell cycle are used in the treatment of leukemia.

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Differences lead to drug tolerance

According to the traditional view, the stem cell-like, undifferentiated properties of cancer cells make them resistant to therapies. However, in this study, inhibition of WEE1 led to resistance or drug tolerance in some cancer cells by promoting their differentiation.

Next, researchers are looking for drugs that target this drug tolerance state. Repeated targeting of such drugs to the WEE1 inhibitor effectively prevented drug tolerance and relapse of cancer cells after treatment and induced their death in cell and animal models of leukemia.

“Our goal is to shed light on the underlying mechanisms of diseases associated with disturbances in the regulation of cell levels. These findings show that ineffective drug responses may be associated with the transition of cancer cells to a cell state that is more tolerant to drugs,” says the professor. Merja Heinäniemi from the Department of Biomedical Sciences, University of Eastern Finland.

Observations made in the research project shed light on gene regulation, cell cycle regulation and interactions between cells. Based on the results, combining the WEE1 inhibitor with other targeted drug therapies may improve treatment and reduce side effects.

Most important collaborators in the study Olle Sangfeldt From the Carolinian Institute, Anna Hagstrom-Andersen from Lund University and Olli Lohi with its research teams from the University of Tampere.

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