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Updated: Apr 1, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer

R Polanski1, J Vincent1, U M Polanska1

  • 1AstraZeneca, Oncology Bioscience iMed, Alderley Park, Macclesfield, UK.

Cell Death & Disease
|October 2, 2015
PubMed

Insights

Predictive biomarkers are needed for cancer therapies combining TRAIL receptor agonists (TRA) and IAP inhibitors (IAPi). This study found Caspase-8 activity predicts response to AZD5582+TRAIL, suggesting a functional assay for patient selection.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) and SMAC mimetics show promise in cancer therapy.
  • Predictive biomarkers for combination therapies involving TRAIL receptor agonists (TRA) and inhibitors of apoptosis proteins (IAP) inhibitors (IAPi) are lacking.

Purpose of the Study:

  • To identify predictive biomarkers for the synergistic combination of TRAIL and the IAPi AZD5582 in breast cancer.
  • To investigate the mechanisms of resistance to this combination therapy.

Main Methods:

  • High-throughput screening of 31 breast cancer cell lines for synergy between TRAIL and AZD5582.
  • Analysis of protein expression levels and functional assays including Caspase-8 activity.
  • Development and validation of a 3D spheroid assay for ex vivo biomarker analysis.

Main Results:

  • Approximately 30% of cell lines exhibited synergistic activity with AZD5582 and TRAIL.
  • Resistance to the combination was linked to impaired Caspase-8 activation downstream of the TRAIL receptor, not protein expression levels.
  • A 3D spheroid assay effectively measured Caspase-8 activity as a predictive biomarker.

Conclusions:

  • The functionality of the TRAIL receptor pathway, specifically Caspase-8 activation, is critical for predicting response to IAPi+TRA combination therapy.
  • Caspase-8 activity assays offer a superior predictive biomarker approach compared to protein expression analysis for patient stratification.

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