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Their findings, published in , demonstrates the role of activators of ferroptosis in overcoming acquired resistance to FOXM1 inhibitors.

Drug resistance poses a difficult problem for many breast cancer patients by reducing the efficacy of many long-term treatments. Although a given treatment may kill off most cancer cells, a small percentage are resistant to treatment, enabling their survival, growth, and spread.

Cancer cells’ ability to survive and grow relies on a balance between cell proliferation and cell death. Two of the dominant regulatory factors governing the proliferation, growth, and survival of breast cancer cells are estrogen receptor and FOXM1, a cancer-promoting transcription factor highly expressed in many cancers and absent in most normal adult tissues. FOXM1 stimulates cell proliferation but, as they show, it also suppresses cell death, enabling the survival of tumors.

“If you have more cells and they’re dying less well, you get larger and more aggressive tumors,” said , the Swanlund Professor of Molecular & Integrative Physiology and an author of the paper.

Katzenellenbogen’s team wanted to characterize the role of FOXM1 in promoting breast cancer cell survival and aggressiveness to improve clinical outcomes in breast cancer patients. They began by developing FOXM1 inhibitors called NB compounds which bind to FOXM1, blocking its activity. But some breast cancer cells that are initially suppressed by NB compounds become resistant to their killing effects, resulting in the survival and growth of these cancerous cells.

“Cancer cells are very smart cells, so they figure out ways to become resistant to the killing effects of these inhibitors,” Katzenellenbogen said. “They are no longer killed by the inhibitor and instead survive and grow.”

The researchers examined changes in these cells that enabled them to adapt and survive in the presence of an inhibitor. Unexpectedly, global RNA gene analysis revealed that in ER-positive and triple-negative breast cancer cells, resistance to FOXM1 inhibition was accompanied by elevated levels of ferroptosis-suppressing genes. This suggested that acquired resistance to FOXM1 inhibitors could be reversed with inducers of ferroptosis, a type of iron-dependent programmed cell death. Cancer cells are highly dependent on iron for their metabolic activity.

“That encouraged us to look further at the status of ferroptosis in sensitive cells and in cells that had become resistant to the inhibitors,” Katzenellenbogen said. “From every experiment we do, we learn things that are often new and get us looking in new dimensions.”

Although the team’s findings will need to be examined further in in-vivo animal models, they are hopeful that the use of ferroptosis activators may be an effective tool to treat a broad variety of cancers and to enhance therapeutic response to FOXM1 inhibition.

“We are beginning to work in organoids, which are multicellular and mimic more of the natural breast environment in which a cancer would find itself,” Katzenellenbogen said. “And based on that, the next steps would be movement toward clinical trials of safety and then efficacy.”

This research was made possible by an interdisciplinary team including postdoctoral researcher Sandeep Kumar, research specialist Yvonne Ziegler, and undergraduate Blake Plotner in Molecular and Cellular Biology; Swanlund Professor John Katzenellenbogen and research scientist Sung Hoon Kim in the Department of Chemistry; and Kristin Flatt in the Materials Research Laboratory at the University of Illinois.

Benita and John Katzenellenbogen expressed their appreciation for support of this research by the Breast Cancer Research Foundation, the National Cancer Institute at NIH, the Mary and Julius Landfield Cancer Research Fund, and the Cancer Center at Illinois.