Preventing Drug Resistance in Patients With Germline BRCA1 Mutations

It may be possible to remove deleterious germline BRCA1 mutations through alternative mRNA splicing and prevent drug resistance in some breast and ovarian cancer patients. Researchers at Fox Chase Cancer Center are reporting in the May 1, 2016, issue of Cancer Research that patients with mutations affecting a specific portion of the BRCA1 gene may be susceptible to a new pathway of resistance to DNA-damaging drugs, including PARP inhibitors and platinum compounds.

The researchers note that breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefited from therapy with PARP inhibitor or platinum compounds. However, clinical outcomes have been hampered by acquired resistance. In this study, the researchers examined the impact of mutations on BRCA1 isoform expression and therapeutic response. They found that treatment with one compound that reduces levels of a resistance-promoting form of the BRCA1 protein improved the sensitivity of cancer cells.

“The development of effective treatment strategies for breast and ovarian cancer has been limited by an incomplete understanding of what causes resistance to PARP inhibitors and platinum compounds,” said senior study author Neil Johnson, PhD, assistant professor of Molecular Therapeutics at Fox Chase Cancer Center, Philadelphia, in a news release. “By shedding light on this question, our study could pave the way for personalized strategies to predict which patients will develop resistance, and provide an opportunity to re-sensitize breast and ovarian tumors to DNA-damaging drugs.”

Johnson et al. discovered that mutations affecting the exon 11 portion of the BRCA1 gene were particularly susceptible to the development of resistance to PARP inhibitors and platinum compounds. Human breast and ovarian cancer cells with BRCA1-exon 11 mutations were able to express a BRCA1 protein that lacked the exon 11 mutation-containing region. Subsequently, they were less sensitive to cisplatin, as well as the PARP inhibitors rucaparib (investigational drug) and olaparib (Lynparza). The researchers then looked at mouse models harboring the same BRCA1-exon 11 mutations and found that they displayed reduced sensitivity to treatment with cisplatin or rucaparib.

The study demonstrated that the production of BRCA1 proteins that lacked the mutation containing exon 11 region was dependent on alternative splicing. It is now hoped that spliceosome inhibitors may combat drug resistance by preventing the generation of resistance-promoting BRCA1 proteins. The researchers found that human cancer cells with BRCA1-exon 11 mutations showed improved sensitivity to rucaparib when they were also treated with spliceosome inhibitors.

Approximately 30% of BRCA1 mutation carriers who develop breast and ovarian cancer in the United States have BRCA1-exon 11 mutations. These research findings could help to decipher which patients are likely to develop drug resistance to PARP inhibitors and platinum-based compounds.