Le lundi 8 juillet 2024, Monsieur Charles POTTIER, titulaire d’un Diplôme de médecin et d’un Certificat de formation à la recherche en sciences biomédicales et pharmaceutiques, présentera l'examen en vue de l'obtention du grade de Doctorat en sciences biomédicales et pharmaceutiques, sous la direction de Monsieur Nor Eddine SOUNNI et de Monsieur Guy JERUSALEM.

Cette épreuve consistera en la défense publique d'une thèse intitulée :  "Characterization of metabolic alterations of hormone-dependent breast cancer resistant to palbociclib-fulvestrant and its collateral drug susceptibility to ferroptosis"

Le jury sera composé de :

Philippe DELVENNE (Président), Benaïssa EL MOUALIJ (Secrétaire), François DUHOUX (UCLouvain), Guy JERUSALEM, Denis MOTTET, Agnès NOEL, Nor Eddine SOUNNI, Andrei TURTOI (IRC Montpellier).

Résumé de la thèse :

Metastatic HR+ HER2- breast cancer mostly becomes resistant to the first-line treatment: the combination of CDK4/6 inhibitor (palbociclib) and hormone therapy (HT). 

To identify targets that further increase palbociclib-HT efficacy, we utilized biopsies from cancer patients who showed recurrence after treatment, HR+HER2- luminal cancer cells sensitive and resistant to palbociclib-HT, RNAseq analysis, exosome sequencing and proteomics. 

Proteomic analysis of human samples revealed an upregulation of the oxidative stress-triggered proteasome subunit alpha7 (PSMA7) in metastatic relapses in different organs after patient’s resistance to palbociclib-HT combination. In cancer cells, we found that PSMA7 interacts with estrogen receptor (Erα), stabilizes it and increases the degradation of retinoblastoma protein (Rb). RNAseq analysis revealed that resistant cancer cells have increased expression of lipid transport proteins (FABP6, FABP7 and CD36). Increased lipid uptake in pre- and resistant cells was validated by increased lipid droplets. Resistant cells showed acquired resistance to ferroptosis related to the upregulation of GPX4, an anti-ferroptotic protein also found upregulated in biopsies of resistant patients. Importantly, targeting ferroptosis resistance by RSL3 or by eprenetapopt sensitized resistant cells to palbociclib and fulvestrant in vitro, in xenografts and in PDX resistant to palbociclib-HT. 

Together, our findings indicate that the cellular oxidative stress-response mediated by proteasome, GPX4 and lipid uptake drives HR+HER2- breast cancer resistance to cytostatic and cytotoxic effects of palbociclib-HT. Targeting ferroptosis resistance with ferroptosis inducers can be used for improving the efficacy of palbociclib-HT combination in metastatic breast cancer.