Dual CDK and MEK Inhibition potentiates CD8+ T cell-mediated antitumor immunity by inducing pyroptotic cell death in high-mutational head and neck cancer

  • J Exp Clin Cancer Res. 2025 Nov 6;44(1):300. doi: 10.1186/s13046-025-03557-7.
Fanghui Chen  #  1 ,  Fang Yang  #  1 ,  David O Popoola  2 ,  Jianqiang Yang  1 ,  Chris Tang  1 ,  Alexis Payne  1 ,  Lynn Zhang  1 ,  Nicole C Schmitt  3  4 ,  Jin Xie  5 ,  Nabil F Saba  1  4 ,  Yamin Li  6 ,  Yong Teng  7  8  9
Affiliations
  • 1. Department of Hematology and Medical Oncology, Emory University, 201 Dowman Dr, Atlanta, GA, 30322, USA.
  • 2. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
  • 3. Department of Otolaryngology, Emory University, Atlanta, GA, 30322, USA.
  • 4. Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.
  • 5. Department of Chemistry, University of Georgia, Athens, GA, 30602, USA.
  • 6. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA. [email protected].
  • 7. Department of Hematology and Medical Oncology, Emory University, 201 Dowman Dr, Atlanta, GA, 30322, USA. [email protected].
  • 8. Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA. [email protected].
  • 9. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA. [email protected].
  • # Contributed equally.
PMID: 41194215 DOI: 10.1186/s13046-025-03557-7
Abstract

Background: HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous Cancer characterized by high mutational burden, an immunosuppressive microenvironment, and poor response to standard therapies. These features highlight the urgent need for novel and more effective treatment strategies.

Methods: Drug sensitivity prediction was performed using integrated datasets from TCGA, GDSC, and CCLE. To assess the therapeutic potential and underlying mechanisms of combining the CDK Inhibitor AZD5438 with the MEK1/2 inhibitor PD0325901, we employed a comprehensive panel of HNSCC models, including established cell lines, orthotopic mouse tumor models, and patient-derived organoids (PDOs). Lipid nanoparticles (LNPs) were engineered to co-deliver both agents into the same Cancer cell populations. The tumor secretome was profiled using biotinylation coupled with liquid chromatography-mass spectrometry (LC-MS). Molecular alterations were examined by immunofluorescence, immunohistochemistry, ELISA, flow cytometry, and Western blot.

Results: Our bioinformatics analysis identified AZD5438 and PD0325901 as two of thirteen candidate drugs whose sensitivity is consistently associated with the five most frequently mutated genes in HPV (-) HNSCC. Notably, among these candidates, AZD5438 and PD0325901 exhibited the lowest correlation in their sensitivity profiles, suggesting complementary mechanisms of action. In experimental models, the combination of AZD5438 and PD0325901 not only outperformed either monotherapy in suppressing tumor growth but also augmented CD8⁺ T cell-mediated antitumor immunity by promoting Caspase-8/gasdermin E-dependent Pyroptosis. Furthermore, in both orthotopic tumor-bearing mice and PDOs, the LNP-encapsulated drug combination produced significantly greater therapeutic efficacy compared with the free drug formulation.

Conclusions: Our findings indicate that the combination of AZD5438 and PD0325901 holds therapeutic potential for the treatment of HPV (-) HNSCC, particularly in tumors with a high mutational burden. By targeting complementary pathways, this combination may improve treatment outcomes in this aggressive Cancer subtype.

Keywords
AZD5438; Combination therapy; HNSCC; High mutational burden; Lipid nanoparticles; PD0325901; Pyroptosis.
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