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Researchers at the MRC Weatherall Institute of Molecular Medicine have recently discovered why a class of cancer drugs is beneficial only in a subset of patients. The results could pave the way for the future development of these drugs, known as PNP-inhibitors, as personalised medicines.

Digital illustration of a cancer cell and DNA strand

In a study published in Cell Reports, Professor Jan Rehwinkel’s group in the MRC Human Immunology Unit have revealed that only leukaemic cells from patients with SAMHD1 mutations are killed by PNP-inhibitors. The researchers found mutations in a gene coding for a protein known as SAMHD1 to be associated with treatment response. The findings suggest that cancer patients might be able to be tested for SAMHD1 mutations and only those with an inactive version of SAMHD1 in their cancer cells be treated with PNP-inhibitors.

While working on the role of SAMHD1 in the control of viruses, the group’s investigations took an unexpected turn. Doctoral students in the laboratory were comparing cells with and without SAMHD1, which were fed deoxyribonucleotides (dNs). The cells were able to take up and convert these dNs into deoxyribonucleotide triphosphates (dNTPs), the building blocks of DNA. The researchers had set out to investigate how dNTP levels influence virus replication; however, these studies led to a very different observation. Cells without SAMHD1 started dying after feeding with dNs, whereas cells with SAMHD1 were unaffected. After much validation and further characterisation of this observation, the research team concluded that exposure to dNs is an effective way of killing cells that lack SAMHD1.

Cells lacking SAMHD1 were treated with dNs and cell death was monitored with a microscope over time, using green and red dyes that stain dead cells. The images show that dN treatment kills cells without SAMHD1. Cells lacking SAMHD1 were treated with dNs and cell death was monitored with a microscope over time, using green and red dyes that stain dead cells. The images show that dN treatment kills cells without SAMHD1.

The researchers also knew that SAMHD1 is occasionally inactivated by mutations in the cancer cells of some patients, and wondered whether it is possible to selectively kill cancer cells that have SAMHD1 mutations. This led them to discover that cancer cells were killed by dN treatment, but only if they lacked SAMHD1. While these findings using cancer cells grown in the laboratory were encouraging, it was not clear if and how dNs could be used in cancer patients. 

At a molecular level, exposure of cells to dNs leads to an increase in the amounts of dNTPs inside cells. The team showed that this effect is exacerbated in SAMHD1-deficient cells and likely causes the cell death observed. Dr. Tamara Davenne, then a doctoral student working on this project, suggested that this situation mimicked the effects of a class of drug candidates known as PNP-inhibitors. These drugs block the activity of a protein inside cells known as PNP, whose function is to degrade some dNs, particularly deoxyguanosine. PNP inhibitors such as forodesine elevate intracellular dN levels, resulting in higher dNTP concentrations. Forodesine had previously been tested in clinical trials to treat blood and other cancers but unfortunately only showed efficacy in a small subset of cancer patients.

The team were able to confirm that that SAMHD1 prevents build-up of toxic dNTP levels in cells treated with PNP-inhibitors, and that only cancer cells lacking SAMHD1 can be killed with PNP-inhibitors. While promising, this idea will require testing in clinical trials to see if the findings can be translated to the clinic and provide patients with more personalised cancer treatment.

 

This work was funded by the MRC Human Immunology Unit and the Wellcome Trust.