title: Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models.
abstract: BACKGROUND
  Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib.
  
  
  METHODS
  To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration, and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses.
  
  
  RESULTS
  Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration, and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinib-resistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration, and invasion of resistant cells, thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling.
  
  
  CONCLUSIONS
  Complete pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.forename: Lucia
authors.initials: L
authors.lastname: Nappi
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosa
authors.forename: Roberta
authors.initials: R
authors.lastname: Marciano
authors.forename: Claudia
authors.initials: C
authors.lastname: D'Amato
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Amato
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Damiano
authors.forename: Lucia
authors.initials: L
authors.lastname: Raimondo
authors.forename: Francesca
authors.initials: F
authors.lastname: Iommelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Troncone
authors.forename: Bianca
authors.initials: B
authors.lastname: Veneziani
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parsons
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C515233:saracatinib; C508053:ERBB2 protein, human