The first resistance mechanism is described in a paper that was published in the Journal of Clinical Investigation on July 25th. For this study, the team looked at breast tumors that were resistant to the drugs right from the start of the treatment. They focused on different types of errors that can be present in the BRCA1 gene.
NKI researchers discover two new drug resistance mechanisms of BRCA1 breast cancer
26-07-2016
Breast cancer that developed because of an error in the 'cancer gene' BRCA1 can usually be treated quite well with the drug cisplatin and/or PARP inhibitors. But sometimes the tumor does not respond to these drugs, or it becomes resistant to them during the treatment. Why does this happen? The research group of Netherlands Cancer Institute (NKI) researcher Jos Jonkers has discovered two previously unidentified ways in which breast tumors can harbor resistance against cisplatin and PARP-inhibitors.
RING-domain
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.
Epigenetic changes
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.