BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors
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.
Science Foundation Ireland (SFI)/Health Research Board Translational Research Award (TRA-2010-8)
North East Cancer Research and Education Trust (NECRET)
Career Development Award (CDA) from the Conquer Cancer Foundation (CCF) of the American Society of Clinical Oncology (ASCO)
SFI Strategic Research Cluster, Molecular Therapeutics for Cancer Ireland (award 08/SRC/B1410)
British Columbia (BC) Cancer Foundation, the Vancouver General Hospital–University of BC Hospital Foundation (to the OvCaRe ovarian cancer research team in Vancouver)
Dr. Chew Wei Memorial Professorship
Kleberg Center for Molecular Markers
CommentsThe original article is available at https://www.nature.com/
Published CitationCremona M. BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors. Br J Cancer. 2022;127(3):488-499.
Publication Date30 April 2022
- Beaumont Hospital
- Data Science Centre
- Molecular Medicine
- Neurological and Psychiatric Disorders
- Gynaecology, Obstetrics and Perinatal Health
PublisherNature Publishing Group on behalf of Cancer Research UK
- Published Version (Version of Record)