Researchers from Drexel University’s College of Medicine have identified a critical metabolic vulnerability in breast cancer that has spread to the brain, offering a promising new therapeutic target for a disease with few effective treatment options. When this weakness is targeted, cancer cells undergo cell death. The study found that an enzyme called acetyl-CoA synthetase 2, or ACSS2, enables brain metastatic breast cancer cells to evade ferroptosis, a form of iron-dependent cell death. Importantly, this is the first study to demonstrate that breast cancer cells growing in the brain must suppress ferroptosis in order to survive. The findings were recently published in the journal Cancer Research.
In the study, researchers from Drexel University’s College of Medicine and Sidney Kimmel Cancer Center — through the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Research Consortium — discovered that breast cancer cells that spread to the brain rely on a specific metabolic pathway that converts acetate into a form of energy that tumors need to grow, but which also protects from ferroptosis. Taking this a step further, the group found that blocking this pathway prevents cancer cells from surviving in the brain and small molecules targeting ACSS2 can also induce ferroptosis and shrink tumors in preclinical models.
About 10-15% of stage IV breast cancer patients develop brain metastasis, which occur when cancer cells spread from the breast to the brain. Nearly eight out of 10 of these patients face end-stage disease within a year of diagnosis. Brain metastases develop when cancer cells separate from the primary breast tumor and travel along the bloodstream or lymphatic system, ultimately forming new tumors in the brain. Symptoms can include painful headaches, weakness and seizures, cognitive decline, among other issues.
Treating breast cancer that has spread to the brain remains especially challenging. The blood brain barrier, a protective shield that keeps harmful substances from entering the brain, also prevents many cancer therapies from effectively reaching tumors. While radiation and surgery may help alleviate symptoms and reduce the tumor size, these options are ineffective and come with serious side effects impacting quality of life.
Brain tumor growth depends on cells rewiring their metabolism to absorb large amounts of acetate, an energy source for the brain. These cells convert this acetate to acetyl-CoA — a critical building block that fuels tumor growth and provides cancer cells signals to survive using an enzyme known as ACSS2.
The study reveals that this process is regulated by an enzyme called O-GlcNAc transferase (OGT) and a protein kinase involved in neuron growth called cyclin-dependent kinase 5 (CDK5), which together promote phosphorylation — to change the behavior of the enzyme ACSS2. Brain-metastatic breast cancer cells exhibited elevated levels of OGT, O-GlcNAcylation and phosphorylated ACSS2 compared to primary breast cancer cells. Importantly, disruption of OGT or CDK5 significantly impaired tumor growth in the brain.
“Mechanistically, ACSS2 was found to support tumor survival by suppressing ferroptosis, through a protein that regulates gene expression called E2F1-mediated upregulation of the anti-ferroptotic protein SLC7A11,” said Reginato. “Targeting this pathway with a novel, brain-penetrant ACSS2 inhibitor (AD-5584) induced ferroptosis and markedly reduced tumor growth in both ex vivo and in vivo models.”
These findings build on the group’s prior work in glioblastoma, which first established that OGT-dependent phosphorylation of ACSS2 enables tumor cells to utilize acetate for growth in the brain. Together, these studies highlight a conserved metabolic adaptation across tumor types to survive in the brain.
“The enzyme ACSS2 enables tumor cells to exploit brain-specific nutrients to grow,” said senior author Mauricio Reginato, PhD, a professor and chair of Biochemistry & Molecular Biology in Drexel’s College of Medicine. “This work demonstrates a strategy to selectively kill metastatic cancer cells in the brain while sparing normal tissue.”
Previous work by the team showed that new drugs that can get to the brain, inhibit ACSS2, and can shrink breast cancer tumors in the brain of a mouse model.
“The brain presents a unique metabolic environment that cancer cells need to adapt to in order to survive,” said Reginato. “Tumor cells in the brain must compete with surrounding cells for key nutrients, like glucose. Because glucose availability is limited, these cancer cells shift their metabolism to rely on acetate as an alternative fuel source. They convert acetate into acetyl-CoA, a critical metabolite that supports energy production, lipid synthesis and while also regulate gene expression programs that protects from ferroptosis.”
In ferroptosis, the damaged plasma membrane comes apart, leaving iron in the cells to cause outer fat layers of the cells to oxidize causing cell death and localized inflammation.
As combination therapy is typically the best practice in cancer treatment, the team is now working on whether targeting ACSS2 can be combined with radiation therapy and immunotherapy to more effectively eliminate brain metastatic tumors.
“We are very excited about the induction of ferroptosis by our novel ACSS2 inhibitors,” said lead author Riley Young, a doctoral candidate in the Molecular and Cell Biology and Genetics Program at the College of Medicine. “This regulated form of cell death represents an emerging avenue for stimulating immune cell recruitment to the tumor and possibly enhancing cancer immunotherapy that we plan to test in the lab.”
Understanding that breast cancer brain metastatic cells are sensitive to ferroptotic inducers is important, researchers say. “Breast cancer brain metastatic cells are more sensitive to ACSS2 inhibitors and other drugs that induces ferroptosis,” said Reginato, who co-leads the SKCCC Consortium’s Translational and Cellular Oncology Program. “This work represents an important step toward identifying additional ferroptosis-inducing drugs that could be developed as effective therapies.” With further development, this strategy may open the door to more effective treatments for patients facing one of the most aggressive stages of breast cancer.
This research was supported by the National Institutes of Health’s National Cancer Institute U01CA244303, as well as awards from the PA Breast Cancer Coalition and a Coulter-Drexel Translational Research Award. Alexej Dick, Lorela Ciraku, Emily Esquea and Mauricio Reginato are inventors on patents involving ACSS2 inhibitor AD-5584.
In addition to Young and Reginato, other authors on the study include co-first authors Emily M. Esquea, Lorela Ciraku, as well as Jessica Merzy, Nusaiba N. Ahmed, Alexandra N. Talarico, Mangalam Karuppiah, Sophia M. Medori, Rujula P. Warade, Wiktoria Gocal, and Alexej Dick from Drexel’s College of Medicine, and Nicole L. Simone from Thomas Jefferson University’s SKCCC.
The paper, “ACSS2 Suppresses Ferroptosis to Drive Breast Cancer Brain Metastasis” is available here.