Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring. (10th July 2021)

• Record Type: Journal Article
• Authors: Chaudhary, Sanjib; Pothuraju, Ramesh; Rachagani, Satyanarayana; Siddiqui, Jawed A.; Atri, Pranita; Mallya, Kavita; Nasser, Mohd W.; Sayed, Zafar; Lyden, Elizabeth R.; Smith, Lynette; Gupta, Siddhartha D.; Ralhan, Ranju; Lakshmanan, Imayavaramban; Jones, Dwight T.; Ganti, Apar Kishor; Macha, Muzafar A.; Batra, Surinder K.
• Is Part Of: Cancer letters. Volume 510(2021)
• Page Start: 79
• Page End: 92
• Publication Date: 2021-07-10
• Subjects: HNSCC -- Senescence -- Mouse model -- EGFR -- Cyclin D1-CDK4/6; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.04.004
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes. Phosphorylated S6 (p-S6), a downstream effector of EGFR and cyclin D1-CDK4/6 signalling, showed a progressive increase from normal oral tissues to leukoplakia and frank malignancy, and associated with poor outcome of the patients. This increased p-S6 expression was drastically reduced after combination treatment with afatinib and palbociclib in the cell lines and mouse models, suggesting its utiliy as a prognostic marker in HNSCC. Combination treatment also reduced the cell growth and induced cell senescence via increasing reactive oxygen species with concurrent ablation of glycolytic and tricarboxylic acid cycle intermediates. Finally, our findings in sub-cutaneous and genetically engineered mouse model (K14-CreER tam ;LSL-Kras G12D /+ ;Trp53 R172H /+ ) studies showed a significant reduction in the tumor growth and delayed tumor progression after combination treatment. This study collectively demonstrates that dual targeting may be a critical therapeutic strategy in blocking tumor progression via inducing metabolic alteration and warrants clinical evaluation. Highlights: Hyperactive EGFR and cyclin D1-CDK4/6 activates alternative pathway to induce therapy resistance. Phosphorylated S6, downstream effector molecule of EGFR and cyclin D1-CDK4/6 signalling may serve as prognostic marker. Co-treatment with afatinib and palbociclib showed robust cytostatic effect, decreased metabolism, and cellular senescence. Combination therapy reduced or delayed tumor progression in the mouse models.