Researchers uncover new therapeutic vulnerability in endocrine therapy-resistant breast cancers

For patients with estrogen receptor (ER)-positive breast cancer, development of the so-called Y537S mutation signals that their disease has taken an aggressive course and may become resistant to endocrine therapy. Now a preclinical study, led by researchers at UT Southwestern Medical Center, suggests that a class of new drugs already in clinical trials might work especially well in breast cancer patients who have acquired this mutation.

"Identifying drugs that selectively target this highly aggressive mutation has been elusive," said Prasanna Alluri, M.D., Ph.D., Assistant Professor of Radiation Oncology, a member of UTSW's Harold C. Simmons Comprehensive Cancer Center, and senior author of the study published in JCI Insight. "Now we have uncovered a new therapeutic vulnerability in breast cancers that have developed resistance to endocrine therapy through acquisition of the Y537S mutation. When used early, this drug may prevent or delay development of endocrine therapy resistance by blocking an increase in the proportion of cells harboring the Y537S mutation."

In the U.S., over 250,000 patients are diagnosed with breast cancer each year. About 75% of breast cancers are ER-positive, meaning that the growth of these tumor cells is fueled by the binding of estrogen to the estrogen receptor protein in the cytoplasm. This binding results in the ER protein entering the nucleus and altering the on/off status of many genes, stimulating growth of the tumor.

To combat this, patients receive endocrine therapy drugs that block ER function. These drugs usually work well for a time, but in most patients with metastatic breast cancer, tumor cells often develop mutations that allow them to circumvent the drug's effects and continue growing. A common mutation, dubbed Y537S, causes a high degree of resistance to endocrine therapy.

By testing over 1,200 existing drugs or drug candidates against breast cancer cells, UT Southwestern researchers identified a BET inhibitor called OTX015 that significantly suppressed the growth of breast cancer cells – especially those carrying the Y537S mutation. Two other BET inhibitors also showed higher selectivity toward Y537S cells. BET proteins are known to enhance the activity of many genes that drive the proliferation of cancer cells, making them an attractive target for cancer drugs.

OTX015 also showed high effectiveness in inhibiting the growth of tumors harboring the Y537S mutations when implanted in mice. Furthermore, when combined with abemaciclib, a clinically approved drug used to treat breast cancer patients, OTX015 showed higher efficacy in inhibiting tumor growth than the existing standard-of-care treatment.

Our mouse studies showed that OTX015 plus abemaciclib caused 50% greater tumor reduction than fulvestrant plus abemaciclib."

Dr. Prasanna Alluri, M.D., Ph.D., Assistant Professor of Radiation Oncology, UTSW

According to Dr. Alluri, there are several BET inhibitors in early-stage clinical trials, including OTX015, which was shown to be safe in a phase 1 trial.

"This new data can guide the design of BET inhibitor trials by identifying patients who are more likely to respond to this promising treatment. Our study also uncovers promising BET inhibitor combination treatments, which can also be further validated in future clinical trials in breast cancer patients," said Dr. Alluri. "Our hope is that such trials will lead to improvements in both the prevention and treatment of endocrine therapy resistance in patients with breast cancer."

Other UTSW researchers involved in the study include Sm N. Udden, Qian Wang, Venkat S. Malladi, Shuguang Wei, Bruce A. Posner, Sophie Geboers, Noelle S. Williams, Yulun Liu, Jayesh K. Sharma, Ram S. Mani, Srinivas Malladi, Karla Parra, Mia Hofstad, and Ganesh V. Raj.

The study was supported by funds from the Conquer Cancer Foundation, the Breast Cancer Research Foundation, The Cary Council of Southwestern Medical Foundation, and the Department of Defense's Breast Cancer Research Program.

Source:
Journal reference:

Udden, S.N., et al. (2022) Targeting ESR1 mutation–induced transcriptional addiction in breast cancer with BET inhibition. JCI Insight. doi.org/10.1172/jci.insight.151851.

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