Researchers uncover new therapeutic vulnerability in breast cancer resistant to endocrine therapies

Researchers uncover new therapeutic vulnerability in breast cancer resistant to endocrine therapies

For patients with estrogen receptor (ER)-positive breast cancer, the 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 may work particularly 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, MD, Ph.D., assistant professor of radiation oncology, member of the Harold C. Simmons Comprehensive Cancer Center at UTSW and senior author of the study published in JCI Insight. "Now we have discovered 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 can prevent or delay the development of resistance to endocrine therapy by blocking an increase in the proportion of cells harboring the Y537S mutation."

In the United States, 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 driven by the binding of estrogen to the estrogen receptor protein in the cytoplasm. This binding causes the ER protein to enter the cell nucleus and change the on/off status of many genes, thereby stimulating the growth of the tumor.

To counteract this, patients receive endocrine therapy drugs that block ER function. These drugs usually work well for a while, but in most patients with metastatic breast cancer, tumor cells often develop mutations that allow them to bypass the drug's effects and continue to grow. A common mutation called Y537S causes high levels 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 - particularly those carrying the Y537S mutation. Two other BET inhibitors also showed higher selectivity towards Y537S cells. BET proteins are known to enhance the activity of many genes that drive cancer cell proliferation, making them an attractive target for cancer drugs.

OTX015 also showed high efficacy in inhibiting the growth of tumors with Y537S mutations when implanted into mice. In addition, OTX015 in combination with abemaciclib, a clinically approved drug for the treatment of breast cancer patients, demonstrated greater efficacy in inhibiting tumor growth than the existing standard treatment.

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

Dr. Prasanna Alluri, MD, Ph.D., assistant professor of radiation oncology, UTSW

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According to Dr. Alluri has several BET inhibitors in early clinical trials, including OTX015, which was shown to be safe in a Phase 1 study.

"These 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 that can also be further validated in future clinical trials in breast cancer patients," said Dr. Alluri. “We hope that such studies will lead to improvements in both the prevention and treatment of resistance to endocrine therapies 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 the Conquer Cancer Foundation, the Breast Cancer Research Foundation, the Cary Council of Southwestern Medical Foundation and the Department of Defense Breast Cancer Research Program.

Source:

UT Southwestern Medical Center

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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