Prostate Cancers Show Common Genetic Defect, Inspiring New Anti-Cancer Drugs
A research team from Lewis Katz School of Medicine at Temple University (LKSOM) and Fox Chase Cancer Centre found that in prostate cancer, a mutation leading to the loss of just one allele of a tumour suppressor gene known as PPP2R2A is enough to make a tumour caused by other mutations worse.
Tumour suppressor genes encode proteins that help to regulate the cell cycle. During cell division, there are checkpoints where DNA is checked for any potentially harmful mutations that could lead to uncontrolled cell growth, such as in cancer. We inherit two alleles of these genes, one from each parents, and since tumour suppressors are fairly robust, they usually only stop working when mutations affect both these copies. The new research published in the journal Oncogenesis found that in prostate cancer, there is an exception to this two-mutation rule.
The researchers worked on human cells and animal models and found that in prostate tumours, having only one normal copy of PPP2R2A meant the patients did not survive as long as those who had two normal copies of the gene. This was because the cells were more likely to divide and replicate, which fuels cancer progression. The cells couldn’t be checked correctly at the checkpoints, so harmful mutations were allowed to sneak through.
In cells that were completely deficient of PPP2R2A, reconstitution of it ultimately killed prostate cancer cells. The protein could correctly sustain the mitotic checkpoint, to the point where the cellular machinery responsible for separating replicated chromosomes for division collapsed. Restoring the gene caused the centrosomes to weaken, and this combination of a sustained checkpoint and weakened centrosomes resulted in the chromosomes not knowing where to go, and therefore cell death.
The researchers also found that to facilitate their own growth, prostate tumours can kick off a copy of PPP2R2A.
A majority of prostate tumours have only one functional copy of the PPP2R2A gene, and because of it’s high frequency, many patients could benefit from treatments that restore the gene’s activity. Small molecules that could activate the protein have already been identified and have the potential to be developed into drugs. It’s a promising start in the development to find treatment for this type of prostate cancer, but more work is needed.