Elucidating the Clinical Significance and Therapeutic Implications of the Anti-apoptotic BCL2 Family Proteins in Advanced Prostate Cancer
Embargo End Date
2025-10-24
ICR Authors
Authors
Westaby, D
Document Type
Thesis or Dissertation
Date
2024-10-24
Date Accepted
Abstract
Metastatic, or advanced, castration-resistant prostate cancer (mCRPC) is invariably fatal
and novel therapeutic strategies are urgently required. Eradicating cancer cells through
apoptosis should reduce the chance of treatment resistance. BH3 mimetics target the antiapoptotic BCL2 family proteins, including BCL2, MCL1 and BCLXL. There is an unmet
clinical need to identify mCRPC with a vulnerability in the apoptotic machinery that respond
to these therapies. To investigate the clinical significance, biology importance, and
therapeutic implications of the anti-apoptotic BCL2 family proteins in advanced prostate
cancer (PC), I studied a variety of biopsy cohorts, as well as interrogating and manipulating
a range of PC models, including cell lines and patient-derived xenografts in vitro and in
vivo. BCL2 expression was enriched in AR-negative mCRPC with features of lineage
plasticity and associated with worse clinical outcomes. BCL2 expression was regulated by
DNA methylation and driven by Snail and ASCL1. BCL2 inhibition had anti-tumour activity
in some, but not all, BCL2-positive PC models. MCL1 copy number gains were common
in mCRPC and occurred early in PC evolution. These associated with worse clinic outcome
and may predict sensitivity to MCL1 targeting. Irrespective of copy number alterations,
some PC cells were exquisitely sensitive to MCL1 inhibition, warranting further
investigation. A deubiquitinating enzyme siRNA screen identified UCHL3 as a potential
regulator of MCL1 stability, but studies revealed this was driven through a seed-mediated
off-target effect, highlighting the critical importance of robust ‘hit’ validation. These studies
confirmed that targeting BCLXL and MCL1 in combination is a lethal to PC cells and may
be an attractive strategy, if expected toxicity can be mitigated. Nevertheless, UCHL3 was
found to be commonly lost in mCRPC and identified as a novel regulator of RESF1 at
protein level. RESF1 is associated with immune pathways in mCRPC, providing rationale
for future studies in this space.
Citation
2024
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Translational Therapeutic