Newly Discovered Cause of Drug Resistance Could Improve Outcomes for Breast and Ovarian Cancer

PHILADELPHIA (May 1, 2016) — Many patients with breast or ovarian cancer initially benefit from DNA-damaging chemotherapies, but it has not been clear why these treatments lose effectiveness over time. In a new study, Fox Chase Cancer Center researchers showed that patients with mutations affecting a specific portion of the BRCA1 gene were susceptible to a new pathway of resistance to DNA-damaging drugs, including PARP inhibitors and platinum compounds.

The findings, published May 1 in Cancer Research, also revealed that treatment with a compound that reduces levels of a resistance-promoting form of the BRCA1 protein improved the sensitivity of cancer cells to these DNA-damaging drugs.

Neil Johnson, PhD
Neil Johnson, PhD

“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. “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 and his team 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, and were consequently less sensitive to the platinum-containing drug cisplatin, as well as the PARP inhibitors rucaparib and olaparib. Similarly, mouse models harboring the same BRCA1-exon 11 mutations displayed reduced sensitivity to treatment with cisplatin or rucaparib.

Researchers also discovered that the production of BRCA1 proteins that lacked the mutation containing exon 11 region was dependent on a process called alternative splicing. Subsequently, compounds called spliceosome inhibitors could help to combat drug resistance by preventing the generation of resistance-promoting BRCA1 proteins. Human cancer cells with BRCA1-exon 11 mutations showed improved sensitivity to rucaparib when they were also treated with spliceosome inhibitors.

The findings could have broad clinical implications, given that BRCA1-exon 11 mutations represent approximately 30% of the overall number of BRCA1 mutation carriers that develop breast and ovarian cancer in the U.S. The presence of these mutations could be used to predict which patients are likely to develop resistance to PARP inhibitors and platinum compounds, thereby guiding future therapeutic strategies.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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