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Synthetic lethality: A new form of cancer therapy?

By Rose Faure - Medicine Student @ Trinity College, Oxford


It has long been understood that cancer is a disease whereby cells divide uncontrollably, eventually metastasising into surrounding tissues. This uncontrollable cell division is typically the result of mutations to our DNA, with the majority of these dangerous mutations being found within genes. Current chemotherapy drugs designed to treat cancer work by preventing cell growth and multiplication, resulting in cellular death. However, one of the most troubling features of chemotherapy is that it does not just target cancer cells, but instead attacks cells that have a high rate of growth and multiplication. This means that chemotherapy will not just kill cancer cells, but also cells such as blood cells and those in hair follicles and the lining of the digestive tract. This damage to healthy cells is what causes the vast array of negative side effects to chemotherapy. It is therefore evident that a more targeted form of cancer treatment is needed, one which effectively kills cancerous cells without damaging the fast-dividing healthy cells of the body.

Synthetic lethality refers to the biological phenomenon by which a single mutation is not fatal for a cell, but the co-occurrence of this mutation alongside a separate mutation is enough to result in cell death. In the context of cancer, this is particularly useful as it is thought tumour specific mutations could be exploited in order to design anticancer therapies that are lethal to cancer cells, but not to normal cells. This form of treatment is reliant upon the advances we have made in sequencing and identifying the hundreds of tumour specific mutations and alterations in gene expression, as it would be these changes that would be targeted using the principles of synthetic lethality.

Current screenings have been looking at isogenic cell line pairs – these are cells that differ only in a single mutation, and can therefore be studied to see if any genes can be inactivated and result in only the death of the cell with the mutant gene. Whilst this concept seems simple enough, the problem being faced is that these mutations are often context dependant and only occur in the presence of other mutations or in specific cell types. Unfortunately, this begins to limit the clinical utility of synthetic lethality.

Perhaps the most promising lethal interaction that could be utilised for such treatment is that among PARP and BRCA1/2 – the gene which encodes for a DNA repair enzyme, and genes which play a role in cell repair. PARP inhibitors are beginning to be used clinically, and have been seen to utilise synthetic lethality mechanisms in order to result in genetic instability and cell death. PARP inhibitors are currently licenced for treatment of ovarian, fallopian tube, and peritoneal cancer although there are some other cancers that feature a weakness similar to that within the BRCA gene fault, and may therefore also be susceptible to PARP inhibitor treatment. These include lung, pancreatic, and prostate cancer.

Clearly there is a long way to go before synthetic lethality will be the main mechanism of action that clinically used anticancer therapies rely upon. Nonetheless, the research is both ongoing and promising, paving the way for a new, more targeted mode of cancer treatment to replace the current therapies.

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