Targeting ferroptosis resistance re-sensitizes metastatic HR+ HER2- breast cancer to palbociclib-hormone therapy

HR+HER2- breast cancers resistant to palbociclib-hormone therapy displayed increased lipid uptake and expression of stress response proteins (GPX4, PSMA7), by adding ferroptosis inducers to palbocilib-fulvestrant combination therapy, tumor response was enhanced in three different pre-clinical models: resistant cells, xenografts and PDX. Overall design: For the generation of resistant cells, T47D and CAMA-1 were treated with 0.3 µM of Palbociclib (P) and 30 nM of Fulvestrant (F) for 1 and 2 year(s) respectively. Resistance was assessed by proliferation assay with Incucyte. RNAseq was performed with 1) T47D parental, T47D treated with PF for 5 and 20 days and T47D resistant to PF, obtained after 1 year and 2) CAMA-1 parental cells and CAMA-1 treated with PF for 5 and 20 days.