Royal College of Surgeons in Ireland
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BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

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posted on 2023-01-04, 15:29 authored by Mattia Cremona, Cassandra J Vandenberg, Angela Farrelly, Stephen MaddenStephen Madden, Clare Morgan, Roshni Kalachand, Jessica N McAlpine, Sinead ToomeySinead Toomey, David G Huntsman, Liam GroganLiam Grogan, Oscar BreathnachOscar Breathnach, Patrick MorrisPatrick Morris, Mark S Carey, Clare L Scott, Bryan HennessyBryan Hennessy

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.

Funding

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)

Carraressi Foundation

MSFHR

Dr. Chew Wei Memorial Professorship

Myer-Levy Fellowship

Kleberg Center for Molecular Markers

IReL Consortium

History

Comments

The original article is available at https://www.nature.com/

Published Citation

Cremona 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 Date

30 April 2022

PubMed ID

35501389

Department/Unit

  • Beaumont Hospital
  • Data Science Centre
  • Medicine
  • Molecular Medicine

Research Area

  • Cancer
  • Neurological and Psychiatric Disorders
  • Gynaecology, Obstetrics and Perinatal Health

Publisher

Nature Publishing Group on behalf of Cancer Research UK

Version

  • Published Version (Version of Record)