Two new studies published in the Journal of Clinical Investigation revealed the mechanisms by which certain BRCA1 mutations make breast and ovarian cancers resistant to treatments. These new findings may help predict which patients will respond effectively to cancer therapies.
Researchers estimate 5 to 10 percent of all breast cancer cases are hereditary, and the many of those (30-80%) are caused by mutations in the breast cancer 1 or breast cancer 2 (BRCA1 or BRCA2) gene.
In fact, inherited mutations in the BRCA1 gene predispose women to hereditary breast and ovarian cancer, with an 80-90% lifetime risk of developing breast cancer and a 40-50% risk of developing ovarian cancer.
In the study “BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1,” Netherlands Cancer Institute researchers found that mice carrying a specific form of the cancer-associated human BRCA1 mutation, BRCA1184delAG, produced a defective protein that missed a key structural component called a RING domain which in turn enhanced tumors’ resistance to targeted therapies.
In another study titled “RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance,” Fox Chase Cancer Center researchers investigated the same specific BRCA1 mutation and focused on these cells’ treatment resistance.
RING-deficient BRCA1 proteins contributed to the lack of sensitivity to treatments such as platinum and poly (ADP-ribose) polymerase inhibitor (PARPi) therapy, a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase and a common treatment for several cancers, including breast and ovarian.
While it was established that mutations in BRCA1 or BRCA2 genes are associated with a high risk of breast and ovarian cancers and treatment resistance, the mechanisms behind the loss of sensitivity to therapy were not fully understood.
These novel findings provide an important insight into key genetic functions that will hopefully result in a more effective design in future therapies.