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Updated: Nov 19, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative
Kamal Pandey1, Eunbyeol Lee2, Nahee Park1
1Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea.
Abstract:
Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4, and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.
Insights
Genomic and transcriptomic analysis revealed that immune pathway deregulation contributes to resistance against cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer models. This suggests immune pathways as potential therapeutic targets to overcome treatment resistance.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Cyclin-dependent kinase (CDK) 4/6 inhibitors are standard treatment for advanced hormone receptor-positive breast cancer.
- Acquired resistance to CDK4/6 inhibitors is a major clinical challenge, limiting long-term patient benefit.
Purpose of the Study:
- To identify genes and pathways associated with palbociclib resistance using integrated genomics and transcriptomics.
- To explore novel mechanisms of resistance beyond known pathways like RB loss or Cyclin E-CDK2 activation.
Main Methods:
- Generation of palbociclib-resistant breast cancer cell lines.
- Whole-exome sequencing (WES) and mRNA microarray analysis to compare sensitive and resistant cells.
- Pathway analysis of differentially expressed genes (DEGs) and mutated genes.
Main Results:
- Identified 651 DEGs and 107 clinically significant mutated genes.
- Pathway analysis revealed significant immune pathway deregulation in resistant cells, including altered type I interferon signaling and immune checkpoint pathways.
- Mutations in NCOR1, MUC4, and MUC16 were linked to immune pathway alterations.
Conclusions:
- Deregulated immune pathways represent an additional mechanism contributing to CDK4/6 inhibitor resistance in breast cancer.
- Targeting immune pathways may offer a novel strategy to overcome palbociclib resistance.
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