title: Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.
abstract: OBJECTIVE
  The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation.
  
  
  OBJECTIVE
  (1) To determine the role of oncogene dependence on PIK3CA-one of the more common and targetable oncogenes in HNSCC, and (2) to evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies.
  
  
  METHODS
  This was a cell culture-based, in vitro study performed at an academic research laboratory assessing the viability of PIK3CA-mutated head and neck cell lines when treated with targeted therapy.
  
  
  METHODS
  PIK3CA-mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235.
  
  
  METHODS
  Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R.
  
  
  RESULTS
  Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred increased, rather than reduced, IC50 assay measurements when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared with the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared with control, whereas those expressing E545K showed slightly increased sensitivity of unclear significance.
  
  
  CONCLUSIONS
  (1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared with control with dual PI3K/mTOR inhibition. (2) Oncogene addiction to PIK3CA hotspot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified. Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of PI3K-overactive HNSCC tumors.
authors: Department of Otolaryngology-Head and Neck Surgery, Tripler Army Medical Center, Honolulu, Hawaii.
authors: Eric D
authors: ED
authors: Wirtz
authors: Kanagawa Cancer Center, Division of Cancer Cell Research, Yokohama, Kanagawa, Japan.
authors: Daisuke
authors: D
authors: Hoshino
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Anthony T
authors: AT
authors: Maldonado
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Darren R
authors: DR
authors: Tyson
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors: Alissa M
authors: AM
authors: Weaver
mesh_terms: D016227:Benzoquinones / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007191:Indazoles / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D000077195:Squamous Cell Carcinoma of Head and Neck; D013449:Sulfonamides / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D007191:Indazoles; D047029:Lactams, Macrocyclic; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011728:Pyridones; D011744:Pyrimidinones; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C560077:trametinib; C112765:tanespimycin; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C531198:dactolisib