November 20, 2014

Gene mutation linked to breast cancer therapy resistance

A group of Vanderbilt-led investigators has identified a new gene mutation that may explain why some breast cancer patients do not respond to anti-hormone therapy.

Carlos L. Arteaga, M.D., left, Justin Balko, Pharm.D., Ph.D., Luis Schwarz, M.D., and colleagues are studying a gene mutation that may shed light on why some breast cancer patients don’t respond to anti-hormone therapy. (photo by Joe Howell)

A group of Vanderbilt-led investigators has identified a new gene mutation that may explain why some breast cancer patients do not respond to anti-hormone therapy.

The study was published online in the Journal of Clinical Investigation. Luis Schwarz, M.D., and Emily Fox, Ph.D., served as co-first authors of the study, led by senior author Carlos L. Arteaga, M.D., director of the Breast Cancer Program and the Center for Cancer Targeted Therapies at Vanderbilt-Ingram Cancer Center, along with colleagues at the University of Texas M.D. Anderson Cancer Center, Houston, and Emory University, Atlanta.

Many breast cancer patients have tumors that are fueled by hormones such as estrogen, which binds to estrogen receptors (ER) in tumor cells. The receptors activate ER-dependent genes that, in turn, help ER-positive (ER+) cancers grow.

ER+ tumors often respond to anti-estrogen agents like tamoxifen, fulvestrant or aromatase inhibitors such as letrozole, anastrazole or exemestane. These drugs, referred to as endocrine therapy, are widely used by patients with early and advanced breast cancer.

However, a significant fraction of patients with ER+ metastatic breast cancer don’t respond to endocrine therapy because their tumors are initially resistant or acquire drug resistance after an initial response to anti-estrogens. To identify genetic alterations that help explain this resistance, the investigators profiled ER+ breast tumors from four patients who were treated with the aromatase inhibitor letrozole prior to their mastectomies. These tumors did not respond to the letrozole as measured by markers of proliferation in the mastectomy specimens.

The investigators performed deep sequencing on the tumors and identified a novel mutation (D189Y) in a gene of the Src family of kinases called LYN.

“Src family kinases like LYN are known to be associated with carcinogenesis, cancer cell invasion and metastatic progression,” said Schwarz, a postdoctoral research fellow at VICC.

The investigators also identified other LYN mutations in breast tumors in the Cancer Genome Atlas. Like D189Y, these mutations increase the activity of the LYN protein.

“When present in ER+ breast cancer cells, these mutations induce an advantage in proliferation of cells as well as resistance to anti-estrogen therapies,” said Schwarz. “To the best of our knowledge, no one had previously described how these LYN mutations work.”

The authors tested assays in three cell lines and in a mouse model to identify potential therapies for ER+ breast cancers harboring D189Y LYN. They tested two Src inhibitors and identified the drug dasatinib as the most effective. Since dasatinib is already approved for another form of cancer, it could be adapted for testing in breast cancer.

The authors note that the agent is not an ideal drug because it is not a pure LYN inhibitor. However, they hope that their identification of the new LYN mutation will spur development of a LYN inhibitor for testing in patients with breast cancer.

“Our findings suggest that a LYN inhibitor could be an effective treatment when combined with endocrine therapies in patients with breast cancer,” said Arteaga, also the Donna S. Hall Professor of Breast Cancer Research.

The authors include Justin Balko, Pharm.D., Ph.D., Joan Garrett, Ph.D., Maria Gabriela Kuba, M.D., Monica Valeria Estrada, M.D., Monica Red-Brewer, Ph.D., Ingrid Mayer, M.D., Vandana Abramson, M.D., Mark Kelley, M.D., Ingrid Meszoely, M.D., Vanderbilt; Ana María González-Angulo, M.D., Gordon Mills, M.D., Ph.D., M.D. Anderson Cancer Center; and Monica Rizzo, M.D., Emory University.

Support for the study included funding from the National Cancer Institute, a division of the National Institutes of Health (P50 CA098131, P30 CA68485, P30 CA016672), Susan G. Komen for the Cure, the Breast Cancer Research Foundation, the American Cancer Society and the Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú.