Journal
BRITISH JOURNAL OF CANCER
Volume 127, Issue 3, Pages 488-499Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-022-01823-5
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Funding
- Science Foundation Ireland (SFI)/Health Research Board Translational Research Award [TRA-2010-8]
- North East Cancer Research and Education Trust (NECRET)
- Conquer Cancer Foundation (CCF) of the American Society of Clinical Oncology (ASCO)
- SFI Strategic Research Cluster, Molecular Therapeutics for Cancer Ireland [08/SRC/B1410]
- British Columbia (BC) Cancer Foundation
- Vancouver General Hospital-University of BC Hospital Foundation
- Carraressi Foundation
- MSFHR
- Myer-Levy Fellowship
- Kleberg Center for Molecular Markers
- IReL Consortium
- Dr. Chew Wei Memorial Professorship
- Science Foundation Ireland (SFI) [TRA/2010/8] Funding Source: Science Foundation Ireland (SFI)
- Health Research Board (HRB) [TRA-2010-8] Funding Source: Health Research Board (HRB)
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The study found that XIAP protein expression is increased in BRCA1-mutated cancers, associated with optimization of PARP and NF-kB activation. BRCA1-mutated cells are more sensitive to IAP inhibitors, and treatment with IAP inhibitors can restore the efficacy of PARP 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.
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