Synthetic Lethality: Tipping Cancer Over The Edge

Cancer is a genetic disease and many of the risk factors for cancer exert their tumorigenic effects by increasing the rate of mutations in DNA. Different forms of mutations can cause cancer depending on the type of genes they affect but the end result is the same; rapid and uncontrolled cell proliferation. Loss of function mutations in tumour suppressor genes remove the brakes from cell division whereas gain of function mutations in proto-oncogenes put the foot down on the accelerators.

The key thing to remember about tumours is that there is a miniature evolutionary battle going on between the tumour cells. For every cell to divide, DNA must be replicated and segregated into daughter cells and every time DNA is replicated errors are introduced into the sequence. Hopefully you can see how, because of the sheer number of cell divisions occurring in tumours, there are huge number of mutations being accrued inside tumours. This results in a highly diverse population of cells; each cell will have a slightly different genome to their neighbours. Where there is variation, there is evolution by natural selection. The tumour cells that can survive, proliferate, metastasise and form blood vessels are able to ‘reproduce’ more than the cells that have deleterious or weakening mutations. As a consequence, over time the tumour cells that are the ‘fittest’ (and most dangerous to us) end up making up the majority of tumour. Cancer cell evolution (or branched evolution) is bad news – it explains how tumours can develop resistance to cancer drugs. Is there an upside for us in cancer cell’s messy and error-prone DNA replication?

Cancer Research UK.

Synthetic lethality refers to where a cancer cell has acquired mutations in a specific pathway that makes the cell completely dependent on another pathway for its survival and proliferation. Imagine someone who needs to get to work for 7am and their car is in the garage undergoing repairs, this makes catching the train crucial for them to get to work. If that 2nd pathway is disrupted the cell can no longer survive – in our analogy the train is cancelled, and the person can’t get to work on time.

PARP inhibitors are the only synthetic lethality therapy to make it to the clinic so far. These block poly(ADP-ribose) polymerases – enzymes that sense DNA damage (such as breaks in the helix), bind to the damaged DNA and synthesise chains of ADP-ribose. These chains then act as recruitment signals for proteins that can repair the damaged DNA. The BRCA mutations that can cause breast and ovarian cancer lead to a loss of BRCA function. BRCA proteins are involved in a different DNA repair pathway (known as homologous recombination) so when these proteins are lost healthy cells acquire mutations that allow them to proliferate and form tumours. While the loss of BRCA gene expression pulls cells down a a cancerous path it also makes them highly reliant on poly-(ADP-ribose) polymerases (PARPs) to detect the DNA damage and facilitate repair as too much DNA damage will kill the cells. Researchers at the University of Sheffield were among the first to describe how inhibiting PARPs could kill BRCA2- deficient tumours in a paper published in Nature back in 2008. The first clinical trial, in 2009, found 63% of the patients with BRCA mutant tumours demonstrated a clinical benefit with less side effects than conventional chemotherapy regimens. After further large-scale studies the FDA approved the PARP inhibitor olaparib for some cases of ovarian cancer in 2015. In a further boost for synthetic lethality as an approach, researchers realised that some tumour cells that don’t have BRCA mutations do have a sort of ‘BRCAness’ in that they have a defect in the same DNA repair pathway. They become similarly reliant on other pathways, including poly(ADP-ribose) polymerases. Promising results have been reported for metastatic prostate cancer and in January the European Medicines agency expanded the approval for olaparib to more forms of breast cancer.

O’Neil, NJ & Bailey, ML & Hieter, P. Synthetic lethality and cancer. Nature Reviews Genetics (2017) 18: 613-623pp.

However, we can’t lose sight of the evolution occurring within tumours that allow them to become resistance to PARP inhibitors and the real challenge for new therapies is finding these redundant pathways. The massive numbers of different mutations that can cause cancer makes this difficult and there will be a need for routine DNA sequencing of tumours to achieve real success.
One thing synthetic lethality allows, in theory at least, is the repurposing of drugs. Huge numbers of molecules are dumped on the scrapheap after years, and millions of pounds, have been spent optimising them and testing their safety.  If we can find synthetic lethal interactions for tumour mutations and have drugs already been shown to be safe in humans that hit pathways the cancer cells rely on, the time to the clinic and costs would be slashed. The lessons learnt from PARP inhibitors will hopefully inform future synthetic lethality efforts enabling it to fulfill its potential as a valuable weapon in the fight against cancer.

 

Creative Biolabs.

Jack Gordon

Biomedical science undergraduate interested in genetics, neuroscience, cancer research and the pharmaceutical industry.