Boston, MA (Scicasts) - A study by researchers at Dana-Farber Cancer Institute have illuminated a specific mechanism by which oestrogen receptor-positive (ER+) breast cancers can become resistant to standard therapies and metastasize.

The scientists say the mechanism explains why breast cancers with mutations in the ER gene itself — the target of drugs such as aromatase inhibitors and tamoxifen — become resistant to these therapies and are prone to become metastatic. Resistance to therapy for ER-positive breast cancer is a common cause of breast cancer mortality and a major unmet need.

Dr. Myles Brown, director of the Center for Functional Cancer Epigenetics at Dana-Farber, and Dr. Rinath Jeselsohn, of Dana-Farber's Susan F. Smith Center for Women's Cancers, led a research team reporting the findings in Cancer Cell.

A majority of women with breast cancer have tumours that are fuelled by the hormone oestrogen. Most are treated with therapies that prevent oestrogen production or block the oestrogen receptor in cancer cells to prevent binding by oestrogen, with the goal of starving the tumour of oestrogen and interrupting cancer growth.

Such endocrine therapies, including tamoxifen and aromatase inhibitor drugs, can prevent recurrence of early breast cancer, and can slow the progression of metastatic disease. However, in about one-third of patients with metastatic ER-positive breast cancer, treatment with endocrine therapies leads to the emergence of tumour cells that grow even in the absence of oestrogen hormone, resulting in treatment-resistant disease that is often incurable.

In studying the molecular causes of resistance to endocrine therapies, scientists found DNA mutations in the oestrogen receptor gene in a substantial number of patients with ER-positive breast cancer. In 2013, Jeselsohn and colleagues reported finding ER mutations in the tumours of women with metastatic ER-positive breast cancer. The scientists then created laboratory models of breast cancer to investigate how the mutations (which they estimate occur in about a third of women with metastatic ER-positive breast cancer) cause treatment resistance. In these experiments they found that the mutations caused the tumours to be resistant to the drugs tamoxifen and fulvestrant (another oestrogen-blocker) and oestrogen deprivation.

In the new report, however, the Dana-Farber scientists revealed another previously unknown effect of three of the mutations in the ER gene. That is, the mutations not only cause resistance to oestrogen blockade, but also turn on genes that drive the breast tumours to metastasize to other organs. This kind of unexpected additional action of a mutated gene is termed "neomorphic."

"That tells us that even though the drug therapies are selecting tumours that can grow without oestrogen, the mutations also confer a metastatic advantage to the tumour," explains Brown.

The researchers then used the CRISPR-Cas9 gene editing tool to launch a search to identify which genes are essential in cells with the ER mutations. Among the essential genes they found, CDK7 was of particular interest because it was a potential drug target. In fact, Dana-Farber colleague Dr. Nathanael Gray, and his team had previously developed an experimental CDK7 inhibitor called THZ1. Tests in cell culture and in animal models with transplanted breast tumours showed that the combination of THZ1 and the endocrine blocker fulvestrant slowed growth of tumours more strongly than either agent alone.

"These results support the potential of this combination as a therapeutic strategy to overcome endocrine resistance caused by the ER mutants," say the authors of the report.

Jeselsohn said that clinical CDK7 inhibitors are being developed, and that "we hope to test these drugs and develop a clinical trial for patients with ER-positive metastatic breast cancer."

Article adapted from a Dana-Farber Cancer Institute news release.

Publication: Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery. McDonnell, DP et al. Cancer Cell (12 February 2018). Click here to view.