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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16976
    GDC-0339
    99.87%, Pim Inhibitor
    target: Pim
    Research Areas: Cancer