A study carried out by researchers from the team of Dr Nor Eddine Sounni, Cancer Metabolism and Tumor Microenvironment Group at the GIGA Institute and the ICAB-CHU of Liège, has highlighted a potential strategy to overcome resistance in the most common subtype of metastatic breast cancer. This study, published in Cancer Communicationsidentifies ferroptosis, a new form of programmed cell death dependent on iron and the accumulation of lipid peroxides, as a promising therapeutic avenue to treat cancer cells that have become resistant to standard therapies.
Metastatic hormone-dependent breast cancer (HR+ HER2-) often initially responds to a combination of a cyclin-dependent kinase 4/6 (CDK4/6i) inhibitor, such as palbociclib, and endocrine 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 this study, the research team investigated the resistance mechanisms of HR+ HER2- breast cancer by exposing cancer cells to palbociclib and fulvestrant over a period of two years. Their results revealed that resistant cells exhibited increased oxidative stress and increased lipid uptake. Key proteins responsible for lipid transport, such as FABP6, FABP7 and CD36, were overexpressed 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 found that cells resistant to hormonal therapy combined with palbociclib become more vulnerable to ferroptosis inducers“said Dr. Nor Eddine Sounni, PhD, senior author of the study.”This suggests that targeting ferroptosis could be an attractive approach to overcome resistance and improve outcomes for patients with HR+ HER2 metastatic breast cancer.-.”
Further investigations showed that cancer cells resistant to palbociclib-HT 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 patient-derived xenografts, was shown 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 of Liège
“These results provide strong evidence that ferroptosis inducers, when used in combination with standard therapies, could represent a new treatment strategy for patients whose cancers have become resistant to palbociclib and hormonal therapy.”added Prof. Guy Jerusalem, MD, PhD, co-author of the study and head of the Medical Oncology department at Liège University Hospital.
-This advance opens new perspectives for precision medicine in the treatment of HR+ HER2- breast cancer. Next steps involve optimizing the combination of the ferroptosis inducer with CDK4/6i and HT before potentially initiating a clinical trial to evaluate the effectiveness of ferroptosis inducers in overcoming resistance to therapies in female patients. .
The research team is currently collaborating with the Curie Institute and discussions are ongoing with the Gustave Roussy Institute in Paris to explore clinical applications and further refine this potential therapeutic approach.
Reference
Targeting ferroptosis resistance resensitizes metastatic HR(+)HER2(-) breast cancer cells to palbociclib-hormone therapy.
Pottier C, Montero-Ruiz L, Jehay R, Wery C, Baiwir D, Mazzucchelli G, Bekisz S, Thissen R, Josse C, Rorive A, Gofflot S, Dahmani A, Morisset L, Collignon J, Delvenne P, Marangoni E, Christmas A, Jerusalem G, Sounni NE.
Cancer Commun (Lond). 2025 Jan 13. doi: 10.1002/cac2.12646. Online ahead of print.
