A study by the Netherlands Cancer Institute, in collaboration with international researchers including Ross Chapman of WTCHG, has discovered why some tumours develop resistance to an important class of anti-cancer drugs.
In the normal course of the cell cycle, or as a result of radiation or other environmental factors, strands of DNA often suffer damage. The cell has an efficient repertoire of molecular mechanisms for checking for breaks and repairing them accurately so that their sequence is preserved. Mutations to the genes that generate these pathways can disrupt DNA repair, leading to the further mutations that cause cells to grow out of control and form tumours.
The BRCA1 gene is one of these DNA repair genes. Women with breast cancer caused by mutations in BRCA1 can be treated with PARP inhibitors, a new class of personalised medicine that exploits the DNA repair defects harboured by BRCA1-deficient cells, leading to their selective self-destruction. But some tumours appear to become resistant to PARP inhibitors, and the researchers wanted to find out why.
They dosed mouse tumour cells with PARP inhibitors, and screened for genes whose disruption led to resistance to this treatment. As they reported in a recent issue of Nature, a protein called Rev7 was often missing in the cells that survived. Subsequent experiments showed that Rev7 inhibits DNA end resection, the process by which a cell normally degrades one strand of the DNA on either side of a DNA double-strand break to enable it to be repaired by homologous recombination, the DNA repair pathway inactivated by BRCA1 mutation.
The team went on to find that Rev7 normally functions in a different DNA repair context, the immune system, where inaccurate DNA repair is actually vital and enables our immune cells to generate antibodies of different function and specificity.
‘Our discovery shows that the problem that causes cancer in people harbouring BRCA1 mutations stems from an inability to counteract a DNA repair process that is extremely important for the normal functioning of our immune systems’ says Chapman, who runs a research group on chromatin and genome integrity at WTCHG. ‘By understanding how this works, we can now predict a repair system whose loss can lead to resistance to a new and extremely promising class of anti-cancer drug.’
This work suggests that in future it may be important to screen patients for both BRCA1 and Rev7 mutations before deciding whether to prescribe PARP inhibitors.