New Mechanism Offers Insight into Breast Cancer Treatment Resistance

New research provides insight into a mechanism by which estrogen receptor-positive (ER+) breast cancers can become resistant to therapy and metastasize, as well as potential therapeutic targets, according a study published in Cancer Cell.
Patients with ER+ breast cancer typically receive treatment with endocrine therapies such as tamoxifen and aromatase inhibitor drugs. However, in some patients, treatment with these therapies can cause tumor cells to grow even in the absence of estrogen, which leads to treatment-resistant disease.
Previous studies have pointed to DNA mutations in the estrogen receptor gene in a significant number of patients with ER+ breast cancer as contributors to treatment-resistant disease. Researchers estimate these mutations occur in approximately one-third of women with metastatic ER+ breast cancer, according to the study. In laboratory models, researchers determined that the mutations caused tumors to be resistant to the drugs tamoxifen and fulvestrant, another estrogen blocker, and estrogen deprivation.
In the current study, researchers from Dana-Farber Cancer Institute discovered a previously unknown effect of 3 of the mutations in the ER gene. In addition to causing endocrine resistance, the mutations also turn on genes that cause the breast tumors to spread to other organs in the body, an action termed as “neomorphic,” according to the researchers.
“That tells us that even though the drug therapies are selecting tumors that can grow without estrogen, the mutations also confer a metastatic advantage to the tumor,” study author Rinath Jeselsohn, MD, of Dana-Farber’s Susan F. Smith Center for Women’s Cancers, said in a press release about the findings.
Using the CRISPR-Cas9 gene editing tool, the researchers found that the CDK7 was an essential gene in cells with ER mutations, making it a potential drug target. In a previous study testing an experimental CDK7 inhibitor, the drug was shown to slow the growth of tumors more strongly when used in combination with fulvestrant, compared with either agent alone.
The results show promise in moving closer to a therapeutic strategy to overcome treatment resistance by ER mutations, the researchers noted. The next step would be to launch a clinical trial to test clinical CDK7 inhibitors, which are currently being developed, in patients with ER+ metastatic breast cancer.
Jeselsohn R, Bergholz JS, Pun M, et al. Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations. Cancer Cell. 2018. Doi:
Study sheds new light on mechanism of breast cancer treatment resistance [news release]. Dana-Farber Cancer Institute’s website. Accessed October 3, 2018.

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