title: Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status.
abstract: Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has shown modest activity in most patients.
  
  
  
  Here we investigated the activity of afatinib, a second-generation irreversible pan-EGFR family kinase inhibitor, alone or in combination with ionizing radiation, toward pancreatic cancer cells.
  
  
  
  The influence of afatinib on cell proliferation, cell cycle distribution, clonogenic survival, nuclear fragmentation, ploidy, and centrosome amplification following irradiation was determined. Expression and phosphorylation of HER receptors, Akt, DNA-PKcs, and ERK1/2 was characterized by Western blot analysis.
  
  
  
  Afatinib was growth-inhibitory for all three cell lines but cytotoxic only toward BxPC3 (KRAS (wt)) and Capan-2 (KRAS (mut)) cells, both of which express high levels of EGFR, HER2, and HER3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells, prevented the radio-induced phosphorylation of Akt, and induced mitotic catastrophe following irradiation. In comparison, Panc-1 cells (KRAS (mut)) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization.
  
  
  
  These results must be confirmed in vivo.
  
  
  
  Afatinib showed cytotoxic and radiosensitizing effects toward a subset of pancreatic cancer cells which was closely correlated with expression of EGFR, HER2, and HER3 receptors, but not with KRAS status.
authors.affiliation: Institut Curie, Centre de Recherche, 91405, Orsay, France. florence.huguet@tnn.aphp.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) U612, 91405, Orsay, France. florence.huguet@tnn.aphp.fr.|Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Sorbonne Universités, 75005, Paris, France. florence.huguet@tnn.aphp.fr.|Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Est Parisien, Hôpital Tenon, Service d'Oncologie Radiothérapie, 75020, Paris, France. florence.huguet@tnn.aphp.fr.|Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, 75012, Paris, France. florence.huguet@tnn.aphp.fr.|Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012, Paris, France. florence.huguet@tnn.aphp.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Huguet
authors.affiliation: Institut Curie, Centre de Recherche, 91405, Orsay, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U612, 91405, Orsay, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Fernet
authors.affiliation: Institut Curie, Centre de Recherche, 91405, Orsay, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U612, 91405, Orsay, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Giocanti
authors.affiliation: Institut Curie, Centre de Recherche, 91405, Orsay, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U612, 91405, Orsay, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Favaudon
authors.affiliation: Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Sorbonne Universités, 75005, Paris, France.|Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, 75012, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012, Paris, France.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D000077716:Afatinib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors