New research Shows Ferroptosis Inducers Can Reverse Resistance of the Luminal Metastatic Hormone Positive Breast Cancer

A groundbreaking study led by researchers at Dr Nor Eddine Sounni’s team, Cancer Metabolism and Tumor Microenvironment Group in the GIGA Institute at University of Liège, Belgium, has uncovered a potential strategy to overcome resistance in a common and challenging subtype of luminal (HR+ HER2-) metastatic breast cancer. The study, published in Cancer Communications, identifies ferroptosis, a form of a new programmed cell death dependent on iron and the accumulation of lipid peroxides, as a promising therapeutic avenue for treating cancer cells that have become resistant to standard therapies.

HR+ HER2- metastatic breast cancer often initially responds to a combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), such as palbociclib, and hormone therapy (HT). However, the majority of patients eventually develop resistance to this treatment. Understanding the mechanisms behind this resistance has been a major challenge in oncology research.

In the study, the research team investigated the resistance mechanisms of HR+ HER2- breast cancer by exposing cancer cells to palbociclib and fulvestrant over two years. Their findings revealed that resistant cells exhibited increased oxidative stress and heightened lipid uptake. Key proteins responsible for lipid transport, such as FABP6, FABP7, and CD36, were upregulated in these resistant cells. Additionally, the researchers identified an increase in the expression of GPX4, a critical enzyme that protects cells from ferroptosis, a form of cell death triggered by lipid peroxidation.

“We discovered that cells resistant to the combination therapy palbociclib-HT become more vulnerable to ferroptosis inducers,” said Dr. Nor Eddine Sounni, PhD, senior author of the study. “This suggests that targeting ferroptosis could be a viable approach to overcoming resistance and improving outcomes for patients with HR+ HER2- metastatic breast cancer.”

Further investigations showed that palbociclib-HT resistant cancer cells were more sensitive to ferroptosis inducers, such as RSL3 and Eprenetapopt. "Pharmacological inhibition of GPX4, or depletion of glutathione (GSH) using eprenetapopt (APR246), a clinically safe compound, in xenografts and in patient-derived xenografts, tumors was found to effectively induce cell death in these resistant cancer cells", added the first author of the study Dr Charles Pottier, MD, PhD and clinical researcher at the ICAB-CHU de Liège.

“These findings provide strong evidence that ferroptosis inducers, when used in combination with standard therapies, could represent a novel treatment strategy for patients whose cancers have become resistant to palbociclib and hormone therapy,” added Pr. Guy Jerusalem, MD PhD, coauthor of the study and head of The Oncology Department at CHU de Liège.

This breakthrough opens new doors for precision medicine in the treatment of HR+ HER2- breast cancer. The next steps involve optimization of the combination of the ferroptosis inducer with CDK4/6i and HT before a  potential clinical trial to assess the efficacy of ferroptosis inducers in overcoming therapy resistance in patients.

The research team is now collaborating with Marie-Curie Institute and ongoing discussion with Gustave Roussy Institute in Paris for exploring clinical applications and further refine this potential treatment approach.

Reference

Targeting ferroptosis resistance resensitizes metastatic HR(+)HER2(-) breast cancer cells to palbociclib-hormone therapy.

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Dr. Nor Eddine Sounni