The PARP (poly (ADP-ribose) polymerase) family of nuclear enzymes play key roles in a variety of cellular processes, including DNA repair. Although DNA repair is beneficial in normal, non-cancerous cells, PARP expression and activity are significantly up-regulated in many cancers, suggesting that cancer cells may rely more than normal cells on the activity of PARP, likely because of defects in other DNA repair pathways. PARP inhibitors, including BSI-201 (BiPar Sciences) and olaparib (AstraZeneca) are already showing promise in the treatment of breast, ovarian and prostate cancers linked to faulty BRCA1 and BRCA2 proteins which normally act as tumour suppressors by repairing damaged DNA.
In a study published online on September 16th in the journal EMBO Molecular Medicine, scientists from the Breakthrough Breast Cancer Research Centre at the ICR and the Lombardi Comprehensive Cancer Center, Washington have now shown that PARP inhibitors can also kill cancer cells with mutations in the PTEN (phosphatase and tensin homolog) gene. As with BRCA1/2, the protein encoded by the PTEN gene functions as a tumour suppressor. Cells with faulty PTEN genes were found to be up to 25 times more sensitive to PARP inhibitors than normal cells.
PTEN deficiency was found to cause a homologous recombination (HR) defect in human tumour cells. Amongst other roles, HR acts as a natural safety mechanism that protects chromosomes against damage to the two DNA strands, such as double-strand breaks. Dysfunctions of proteins that facilitate HR are strongly associated with increased susceptibility to several types of cancer – mutations in BRCA1 and BRCA2 also lead to deficiencies in HR. The HR deficiencies caused by reduced PTEN activity were shown to sensitise tumour cells to the effects of PARP inhibitors, both in cell culture experiments and in mouse studies. PTEN is one of the most commonly mutated genes in human cancers and, if clinical trials show that PARP inhibitors are effective in treating patients with PTEN-related tumours, this approach could potentially treat a greater variety of cancers than had previously been thought.