title: Human pancreatic cancer stem cells are sensitive to dual inhibition of IGF-IR and ErbB receptors.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma is a particularly challenging malignancy characterized by poor responsiveness to conventional chemotherapy. Although this tumor frequently overexpresses or possesses constitutively activated variants of IGF-IR and EGFR/Her-2, clinical trials using inhibitors of these receptors have failed. ErbB receptors have been proposed as one mechanism involved in the resistance to IGF-IR inhibitors. Therefore, combined treatment with inhibitors of both IGF-IR and ErbB receptors would appear to be a good strategy for overcoming the emergence of resistance.
  
  
  METHODS
  Sensitivity of cells to NVP-AEW541 and lapatinib in single or combination treatment was assessed by MTT or WST-8 assays in a panel of human pancreatic cancer cell lines and cancer stem cells. Tumorspheres enriched in cancer stem cells were obtained from cultures growing in non-adherent cell plates. The effects on cell signalling pathways were analyzed by Western blot.
  
  
  RESULTS
  We found that combined treatment with the IGF-IR and EGFR/Her-2 inhibitors NVP-AEW541 and lapatinib, respectively, synergistically inhibited pancreatic cancer cell growth. Analysis at molecular level argued in favor of cross-talk between IGF-IR and ErbBs pathways at IRS-1 level and indicated that the synergistic effect is associated with the total abolishment of Akt, Erk and IRS-1 phosphorylation. Moreover, these inhibitors acted synergistically in tumorsphere cultures to eliminate cancer stem cells, in contrast to their resistance to gemcitabine.
  
  
  CONCLUSIONS
  Taken together, these data indicate that simultaneous blockade of IGF-IR and EGFR/Her-2 using NVP-AEW541 and lapatinib may overcome resistance in pancreatic cancer. Thus, the synergy observed with this combined treatment indicates that it may be possible to maximize patient benefit with the appropriate combination of currently known anticancer agents.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain. nurtasun@ub.edu.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain. nurtasun@ub.edu.
authors.forename: Nerea
authors.initials: N
authors.lastname: Urtasun
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain. avidalpla@yahoo.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Vidal-Pla
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain. s.perez-torras@ub.edu.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain. s.perez-torras@ub.edu.|CIBERehd, Madrid, Spain. s.perez-torras@ub.edu.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pérez-Torras
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain. amazo@ub.edu.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain. amazo@ub.edu.|CIBERehd, Madrid, Spain. amazo@ub.edu.
authors.forename: Adela
authors.initials: A
authors.lastname: Mazo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D000077341:Lapatinib; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1