BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors
Menée à l'aide de lignées cellulaires, d'échantillons de tumeurs ovariennes d'origine humaine et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel des mutations des gènes BRCA favorisent la surexpression de la protéine inhibitrice de l'apoptose liée au chromosome X et sensibilisent les cellules cancéreuses aux inhibiteurs de l'apoptose
Background : We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.
Methods : The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models.
Results : Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively.
Conclusion : A clinical trial may be justified to further investigate the utility of IAP inhibitors.
British Journal of Cancer , article en libre accès, 2022