Jonkers and his collogues discovered a specific type of error in BRCA1 that appears to be very important for how the cancer will respond to cisplatin or PARP inhibitors. If the protein that is produced by BRCA1 lacked a characteristic RING-domain, the cancer cells didn't respond to the drug. Tumors with other types of BRCA1 errors did not show this intrinsic resistance. The research was first performed with the help of mouse models for different types of BRCA1 errors, after which it was validated with human breast cancer tissue.
"This discovery can help us to in the future better predict which drugs are best for individual patients", says Jonkers.
The second study by Jonkers' team was published a few weeks earlier, on July 6th, in the Journal of the National Cancer Institute. For this study the researchers looked at tumors that acquired resistance against cisplatin or PARP inhibitors during the treatment. Next to a number of already known resistance mechanisms, they also discovered a previously unknown one. Breast tumors can develop because of an error - a mutation - within the DNA of BRCA1, but it can also arise because of errors in how the gene is regulated. Genes can be turned 'on' or 'off', and can work harder or less hard, by means of so-called epigenetic regulation.
The scientists saw that in breast tumors that developed because BRCA1 was epigenetically turned 'off', the cancer cells sometimes switched BRCA1 back 'on' again during treatment. After this, the cells were resistant against cisplatin and PARP inhibitors. Jonkers: "With this, we show that BRCA1 tumors can not only acquire resistance against these drugs by means of genetic changes - new DNA mutations - but also by means of epigenetic changes." Studies like these offer new clues as to how drug resistance might by overcome, and thus how cancer treatments can be made even more effective.
Both studies that are discussed above were in part made possible with funding by the Dutch Cancer Society.