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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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CDK4/6 inhibition reprograms the breast cancer immunopeptidome via Rb-dependent chromatin and transcriptomic

Robin Minati1, Maxime Cahuzac2, Julie Perrault2

  • 1Institute of Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada; Molecular Biology Program, Université de Montréal, Montréal, QC H3T 1J4, Canada.

Cell Reports
|December 14, 2025
PubMed

Insights

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) reprogram the tumor antigen landscape by enhancing major histocompatibility class I (MHC class I) presentation. This suggests combining CDK4/6is with immunotherapy may broaden antigenic targets in breast cancer.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are standard treatments for metastatic hormone receptor-positive (HR+) breast cancer.
  • The immunomodulatory effects of CDK4/6is are not fully understood.

Purpose of the Study:

  • To investigate the immunomodulatory effects of CDK4/6 inhibition on the tumor antigen landscape.
  • To explore the mechanisms underlying CDK4/6 inhibition-induced changes in antigen presentation.

Main Methods:

  • Utilized multiomics integration (including ATAC-seq) to analyze changes in tumor cells treated with Abemaciclib (a CDK4/6 inhibitor).
  • Investigated the role of retinoblastoma protein (Rb) and BET proteins in mediating transcriptional and chromatin reprogramming.
  • Identified and characterized Abemaciclib-induced MHC class I peptides.

Main Results:

  • CDK4/6 inhibition with Abemaciclib increased MHC class I presentation and reshaped the immunopeptidome in HR+ and triple-negative breast cancer cells.
  • Rb-dependent transcriptional and chromatin reprogramming, involving H3K27 acetylation and enhanced chromatin accessibility, drives these changes.
  • Identified novel immunogenic MHC class I peptides, including those from non-coding regions, increasing tumor immunogenicity.

Conclusions:

  • CDK4/6 inhibition plays a significant role in shaping tumor antigenicity.
  • Combining CDK4/6is with immunotherapy could potentially expand the range of antigenic targets for cancer treatment.
Keywords:
CDK4/6 inhibitorsCP: cancerCP: immunologyabemaciclibbreast cancercancer immunotherapychromatin remodelingimmunopeptidomicsmass spectrometryretinoblastoma proteintumor antigens

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