ArticleJournal of experimental & clinical cancer research : CR2025
Dual CDK and MEK Inhibition potentiates CD8
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed.
- Harmonization and integration of pharmacogenomics screens.Bioinformatics (Oxford, England) · 2026Article
- GLS1 Orchestrates Exosome-Mediated Tumor-Endothelial Communication to Facilitate Angiogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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Authors and funding
12 authors.
Funding
Abstract
backgroundHPV-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.
methodsDrug 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.
resultsOur 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.
conclusionsOur 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.
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