title: Lapatinib in combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ breast tumor xenografts.
abstract: OBJECTIVE
  To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts.
  
  
  METHODS
  Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry.
  
  
  RESULTS
  Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period. In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model.
  
  
  CONCLUSIONS
  Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and that inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively.
authors.affiliation: Department of Radiation Oncology, University of North Carolina at Chapel Hill, NC 27599-7295, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sambade
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
authors.forename: J Terese
authors.initials: JT
authors.lastname: Camp
authors.forename: Eldon
authors.initials: E
authors.lastname: Peters
authors.forename: Chad A
authors.initials: CA
authors.lastname: Livasy
authors.forename: Carolyn I
authors.initials: CI
authors.lastname: Sartor
authors.forename: Janiel M
authors.initials: JM
authors.lastname: Shields
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D066246:ErbB Receptors; D000077341:Lapatinib; D048052:Mitogen-Activated Protein Kinase 3; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases
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