A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity

Science. 2021 Oct;374(6563):eabf2911. doi: 10.1126/science.abf2911. Epub 2021 Oct 1.


We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of cancer-enriched interactions reveals a previously unidentified association of the fibroblast growth factor receptor tyrosine kinase 3 with Daple, a guanine-nucleotide exchange factor, resulting in activation of Gαi- and p21-activated protein kinase 1/2 to promote cancer cell migration. Additionally, we observe mutation-enriched interactions between the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase and PIK3CA (the alpha catalytic subunit of phosphatidylinositol 3-kinase) that can inform the response to HER3 inhibition in vivo. We anticipate that the application of this framework will be valuable for translating genetic alterations into a molecular and clinical understanding of the underlying biology of many disease areas.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Class I Phosphatidylinositol 3-Kinases / genetics*
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Nude
  • Microfilament Proteins / metabolism
  • Mutation
  • Protein Interaction Maps*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Xenograft Model Antitumor Assays


  • CCDC88C protein, human
  • Intracellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3