Targeting Inhibitor of Apoptosis Proteins (IAPs) to Potentiate Immunotherapy in Breast Cancer
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Embargo End Date
2028-03-21
ICR Authors
Authors
Tiu, C
Document Type
Thesis or Dissertation
Date
2025-03-21
Date Accepted
Abstract
Immunotherapy has transformed cancer treatment, improving survival rates in
aggressive triple-negative breast cancer. However, most breast cancer patients do not
respond to immune checkpoint inhibitor (ICI) therapy. Thus, new strategies to enhance
immune activation are urgently needed. Effective treatment requires therapies that kill
cancer cells and mobilise the immune system. Necroptosis, unlike apoptosis, triggers
stronger immune responses by alerting the immune system. To explore immunogenic
cell death (ICD) in breast cancer, I used ASTX660 (tolinapant), a triple inhibitor of IAP
proteins, which are often overexpressed in cancer. My hypothesis was that ASTX660
could sensitise cancer cells to ICD and enhance the efficacy of ICI. The ASTEROID
phase I trial evaluated ASTX660 with pembrolizumab in therapy-resistant patients,
showing a 33% response rate, including 3 breast cancer cases. Analysis of samples
revealed ASTX660’s role in activating RIPK1-Caspase 8-mediated death, upregulating
inflammatory gene expression, and expanding TCR clonotypes. Potential biomarkers of
response included high RIPK3 expression, diverse T cell repertoires, and early increase
in circulating CD57+ effector T cells. Co-clinical studies in Brca1-/-p53-/- murine models
showed ASTX660's effectiveness under necroptotic conditions. I also developed a
method for fresh explants from patient-derived xenograft (PDX) models for ex vivo
assays. Overall, my work highlights pan-IAP inhibition as a promising strategy for improving breast cancer treatment.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Cell Death and Immunity