2. Academic Validation
  3. S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

  • Commun Med (Lond). 2024 Feb 20;4(1):22. doi: 10.1038/s43856-024-00444-8.
Lauren R Begg 1,  Adrienne M Orriols 1 2,  Markella Zannikou 1,  Chen Yeh 1 3 4,  Pranathi Vadlamani 1,  Deepak Kanojia 1 5,  Rosemary Bolin 6 7,  Sara F Dunne 8,  Sanjeev Balakrishnan 9 10,  Roman Camarda 9 11,  Diane Roth 1,  Nicolette A Zielinski-Mozny 1 6,  Christina Yau 9,  Athanassios Vassilopoulos 1 12 13,  Tzu-Hsuan Huang 1,  Kwang-Youn A Kim 1 3,  Dai Horiuchi 14 15 16
Affiliations

Affiliations

  • 1 Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 2 University of Florida College of Medicine, Gainesville, FL, USA.
  • 3 Biostatistics Collaboration Center, Northwestern University, Chicago, IL, USA.
  • 4 Rush University Medical Center, Chicago, IL, USA.
  • 5 Mythic Therapeutics, Waltham, MA, USA.
  • 6 Center for Comparative Medicine, Northwestern University, Chicago, IL, USA.
  • 7 Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • 8 High Throughput Analysis Laboratory, Northwestern University, Evanston, IL, USA.
  • 9 University of California, San Francisco, San Francisco, CA, USA.
  • 10 Pulze.ai, San Francisco, CA, USA.
  • 11 Novo Ventures US, Inc., San Francisco, CA, USA.
  • 12 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
  • 13 AbbVie, Inc., North Chicago, IL, USA.
  • 14 Northwestern University Feinberg School of Medicine, Chicago, IL, USA. [email protected].
  • 15 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. [email protected].
  • 16 Center for Human Immunobiology, Northwestern University, Chicago, IL, USA. [email protected].
PMID: 38378783 DOI: 10.1038/s43856-024-00444-8
Abstract

Background: Understanding why some triple-negative breast Cancer (TNBC) patients respond poorly to existing therapies while Others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies.

Methods: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action.

Results: Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies Pim kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining Pim inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC.

Conclusions: Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting Pim and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16976
    99.77%, Pim Inhibitor
    Pim