Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring

Sanjib Chaudhary, Ramesh Pothuraju, Satyanarayana Rachagani, Jawed A. Siddiqui, Pranita Atri, Kavita Mallya, Mohd W. Nasser, Zafar Sayed, Elizabeth R. Lyden, Lynette Smith, Siddhartha D. Gupta, Ranju Ralhan, Imayavaramban Lakshmanan, Dwight T. Jones, Apar Kishor Ganti, Muzafar A. Macha, Surinder K. Batra

Research output: Contribution to journalArticlepeer-review

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-CreERtam;LSL-KrasG12D/+;Trp53R172H/+) 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.

Original languageEnglish (US)
Pages (from-to)79-92
Number of pages14
JournalCancer Letters
Volume510
DOIs
StatePublished - Jul 10 2021
Externally publishedYes

Keywords

  • Cyclin D1-CDK4/6
  • EGFR
  • HNSCC
  • Mouse model
  • Senescence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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