BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors
- Author(s)
- Cremona, M; Vandenberg, CJ; Farrelly, AM; Madden, SF; Morgan, C; Kalachand, R; McAlpine, JN; Toomey, S; Huntsman, DG; Grogan, L; Breathnach, O; Morris, P; Carey, MS; Scott, CL; Hennessy, BT;
- Details
- Publication Year 2022-08,Volume 127,Issue #3,Page 488-499
- Journal Title
- British Journal of Cancer
- Publication Type
- Research article
- Abstract
- 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.
- Keywords
- Animals; Apoptosis; BRCA1 Protein/genetics; BRCA2 Protein/genetics; Carcinoma, Ovarian Epithelial/drug therapy/genetics; Cell Line, Tumor; Female; Humans; Mice; Mutation; *Ovarian Neoplasms/drug therapy/genetics/pathology; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use; X-Linked Inhibitor of Apoptosis Protein/genetics
- Department(s)
- Medical Oncology
- PubMed ID
- 35501389
- Publisher's Version
- https://doi.org/10.1038/s41416-022-01823-5
- Open Access at Publisher's Site
https://doi.org/10.1038/s41416-022-01823-5- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-10-18 05:06:13
Last Modified: 2024-10-18 05:07:17